Crizotinib

On Aug. 26, 2011, the FDA approved the kinase inhibitor crizotinib (Pfizer’s Xalkori, originally known as  PF-02341066) for treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC), in which tumor cells exhibit rearrangements in the anaplastic lymphoma kinase (ALK) gene. These rearrangements of the ALK gene constitute driver mutations that are critical for the malignant phenotype of lung adenocarcinomas that have the mutations.

Most ALK rearrangements in lung adenocarcinoma result from a deletion and inversion in chromosome 2, which produces EML4-ALK fusion genes. (EML4 refers to the echinoderm microtubule-associated protein-like 4 gene.) EML4-ALK rearrangements are found in about 4% to 5% of patients with NSCLC. This small percentage of lung cancer patients constitutes about 8,000 to 10,000 patients each year in the United States, and a worldwide patient population of around 40,000.

Crizotinib was approved together with a companion diagnostic, Abbott’s Vysis ALK Break Apart FISH Probe Kit, which is designed to help determine if a patient’s tumors have the abnormal ALK gene. The kit is designed to Identify all ALK gene rearrangements with fusion partners, including but not restricted to: EML4, TFG (TRK-fused gene), and KIF5B (kinesin family member 5B).

Crizotinib is the second targeted kinase inhibitor to be approved together with a companion diagnostic in recent weeks.  The first was vemurafenib (Plexxikon/Roche’s Zelboraf,  PLX4032), which we discussed extensively in this blog, and whose approval we covered in our August 19, 2011 article. Vemurafenib was approved together with Roche’s cobas 4800 BRAF V600 Mutation Test.

The discovery of crizotinib began with research at Sugen (San Francisco, CA), which had been acquired by Pharmacia which was subsequently acquired by Pfizer. The drug resulted from research aimed at discovery of a kinase inhibitor that targeted c-Met. The resulting drug, PF-02341066 (later known as crizotinib), is indeed a c-Met inhibitor, and was entered into Phase 1 clinical trials.  c-Met, or hepatocyte growth factor receptor, is a receptor kinase that has been implicated in cancer cell growth, migration, invasion, and metastasis.

Subsequent studies by Japanese researchers identified the inversion that results in the EML4-ALK fusion gene in a subset of human NSCLCs. They also showed that cultured mouse fibroblasts expressing the EML4-ALK fusion gene generated subcutaneous tumors in nude mice. The researchers hypothesized that the EML4-ALK fusion kinase would be a good therapeutic target, as well as a diagnostic biomarker for a companion diagnostic. Meanwhile,  researchers at Pfizer and the Massachusetts General Hospital found that PF-02341066/crizotinib was a multitargeted kinase inhibitor, which targets ALK in addition to c-Met. Pfizer researchers therefore began preclinical and clinical studies aimed at the commercialization of PF-02341066/crizotinib for treatment of patients with NSCLC carrying activating rearrangements of ALK.

Clinical trials of crizotinib in NSCLC patients with activating rearrangements of ALK

The safety and efficacy of crizotinib in NSCLC patients with activating rearrangements of ALK were established in two multi-center, single-arm studies, including a Phase 2 study (PROFILE 1005) and a Part 2 expansion cohort of a Phase 1 study (Study 1001). The studies enrolled a total of 255 patients with late-stage ALK-positive NSCLC. A sample of each patient’s tumor tissue was tested for ALK gene rearrangements before the patient could be enrolled in the study. The studies were designed to measure objective response rate, i.e., the percentage of patients who experienced complete or partial cancer shrinkage. Most patients in the studies had received prior chemotherapy.

In one study, the objective response rate was 50 percent with a median response duration of 42 weeks. In another, the objective response rate was 61 percent with a median response duration of 48 weeks.

The FDA based its approval of the Vysis ALK Break Apart FISH Probe Kit on data from one of the studies.

As part of the post-marketing requirements, Pfizer continues to evaluate critozinib in two confirmatory, randomized, open-label Phase 3 trials. In these trials, crizotinib is being compared with standard-of-care chemotherapy. One study is being carried out in previously treated patients with advanced ALK-positive NSCLC; the other trial is being carried out in previously untreated patients with advanced ALK-positive non-squamous NSCLC.

Crizotinib as a multitargeted ALK/c-Met kinase inhibitor

The epidermal growth factor receptor (EGFR) kinase inhibitors erlotinib (Genentech/Roche’s Tarceva) and gefitinib (AstraZeneca/Teva’s Iressa) are used for the treatment of patients with NSCLC with activating mutations in the intracellular kinase domain of EGFR. As with  crizotinib and vemurafenib, companion diagnostics are used to determine if a patient is likely to benefit from treatment with erlotinib or gefitinib. Activating mutations in EGFR are found in approximately 10–15% of Caucasian and 30–40% of Asian NSCLC patients.

As with most targeted antitumor drugs, acquired resistance to erlotinib or gefitinib develops in patients treated with these agents. The two most common mechanisms of this acquired resistance are:

• development of a secondary mutation that blocks binding of the inhibitors to EGFR kinase (responsible for about 50% of acquired drug resistance)
• amplification and/or activation of the c-Met kinase, or alternatively high-level expression of the natural ligand of c-Met, hepatocyte growth factor (HGF) (responsible for about 20% of acquired drug resistance).

As we discussed in Chapter 5 of our June 2011 book-length report Multitargeted Therapies: Promiscuous Drugs and Combination Therapies, Pfizer researchers and their academic collaborators found in 2010 that one could overcome HGF/c-Met-mediated resistance to erlotinib or gefitinib by combination therapy with an irreversible EGFR kinase inhibitor (such as PF-00299804) and a c-Met inhibitor (such as crizotinib/PF-02341066). The same researchers also developed a rationale for development of a companion diagnostic to identify patients with rare preexisting populations of cells with amplified c-Met genes. Such patients might be treated with the irreversible EGFR kinase inhibitor/c-Met kinase inhibitor combination. This would be expected to bypass the resistance that would develop after standard treatment with erlotinib or gefitinib alone.

Intriguingly, the 2010 Pfizer study thus suggests a second indication for crizotinib–use in combination therapy with an irreversible EGFR kinase inhibitor such as Pfizer’s PF-00299804 to overcome or preemptively circumvent HGF/c-Met-mediated resistance to the approved EGFR kinase inhibitors. However, Pfizer’s PF-00299804 is still in clinical trials, and has not yet been approved by any regulatory agency. Boehringer Ingelheim is also developing an irreversible EGFR kinase inhibitor, and Pfizer has another such agent, neratinib, in clinical trials.

Meanwhile, in addition to crizotinib, there are also other c-Met inhibitors in clinical development, including Daiichi Sankyo/ArQule’s ARQ197 and GSK/Exelixis’ XL880/GSK1363089 (now known as foretinib). ARQ197, which is in Phase 3 trials in NSCLC, is apparently the most advanced compound in development as a c-Met inhibitor.

An important potential use of irreversible EGFR kinase inhibitors is to overcome acquired resistance to first-generation EGFR kinase inhibitors in NSCLC patients due to development of a secondary blocking mutation in EGFR. The development of combination therapies of irreversible EGFR kinase inhibitors with c-Met inhibitors such as crizotinib and ARQ197 would enable their use in overcoming the second major mechanism of acquired resistance to EGFR inhibitors, via HGF/c-Met.

Conclusions

The approval of crizotinib, together with a companion diagnostic, for the treatment of ALK-driven NSCLC represents the newest example of a paradigm shift toward personalized medicine using targeted therapies in the treatment of cancer. Other examples include vemurafenib for the treatment of melanoma, and the original small-molecule targeted kinase inhibitor, imatinib (Novartis’ Gleevec/Glivec) for the treatment of chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GISTs).

In lung cancer, the use of erlotinib and gefitinib to treat EGFR-driven NSCLC, which represents about 10-15% of cases in the U.S. and Western Europe, is yet another example, even though companion diagnostics for these agents had not yet been developed at the time of their introduction to the market. ALK-driven NSCLC represents yet another 4-5% of cases.

According to researchers at the Lung Cancer Mutation Consortium, nearly 60% of patients with lung adenocarcinoma have 1 of 10 genomic abnormalities for which there is an approved or experimental drug. Paul Bunn, M.D., of the University of Colorado School of Medicine (Aurora, CO) asks, “We have 2 drugs approved now for 2 molecular abnormalities. The question is, will we go 10 for 10?”.  Diagnostic technology for testing for these mutations is also moving forward, and according to Dr. Bunn, it is cheaper to test for all ten abnormalities than it used to be to test for one abnormality.

As we discuss in our June 2011 report, and in several articles on this blog, patients treated with targeted agents usually develop acquired resistance to these drugs. Researchers, with some initial success, have been working on developing drugs to overcome this resistance. This is thus an important aspect of the development of personalized medicine for cancer.

Both EGFR-driven and ALK-driven NSCLCs are usually found in non-smokers or light smokers, while most lung cancer is associated with smoking. Physicians who treat lung cancer, as well as patients, await the development of agents that can effectively treat lung cancer in smokers and former smokers. Smoking rates have been going down in many industrialized countries, including the U.S., but that is not uniformly true in all the world. Moreover, there are still large numbers of smokers and former smokers who are at risk for smoking-induced lung cancer, and lung cancer in never-smokers (which accounts for about 10-15% of lung cancer cases) is by no means a solved problem.

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As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.

Vemurafenib

On August 17, 2011 the FDA announced that it had approved the oral targeted therapy vemurafenib (Daiichi Sankyo/Plexxikon/Roche’s Zelboraf; also known as PLX4032) for first-line treatment of metastatic and unresectable melanomas. The drug is indicated for use in patients whose tumors carry the BRAFV600E) mutation. Approximately 50% of melanoma patients have tumors that carry this mutation.

Vemurafenib  was approved together with a test called the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Diagnostics). This is a companion diagnostic designed to determine if a patient’s melanoma cells carry the BRAF(V600E) mutation and thus patients can benefit from therapy with the drug.

Vemurafenib and the companion BRAF(V600E) diagnostic test were approved earlier than scheduled. They had been reviewed under the FDA’s priority review program that provides for an expedited six-month review of drugs that may offer major advances in treatment or that provide a treatment when no adequate therapy exists. The original goal PDUFA (Prescription Drug User Fee Act) review dates for vemurafenib and the companion diagnostic were October 28, 2011 and November 12, 2011, respectively.

The Biopharmconsortium Blog has been following the veurafenib story since March 2010. See this January 23, 2011 article, and the links to earlier articles that it contains.

There are now two drugs approved for the treatment of advanced melanoma in 2011 that demonstrate an improvement in progression-free and overall survival, when before there were none. The other drug, the immunomodulator ipilimumab (Medarex/Bristol-Myers Squibb’s [BMS’s] Yervoy), was discussed in a March 30, 2011 article on our blog.

The FDA granted early approval for vemurafenib on the basis of the results of the pivotal Phase 3 trial known as BRIM-3. In a previous article on this blog, we discussed a report of an interim analysis of this trial in January 2011. The results of the trial were published in the June 30, 2011 issue of the New England Journal of Medicine. Earlier Phase 1 and 2 clinical trails of the drug had show response rates of over 50% in advanced melanoma patients whose tumors bore the BRAF(V600E) mutation.

In the BRIM-3 trial, researchers compared vemrafenib to dacarbazine (the previous standard of care) in 675 patients with previously untreated metastatic melanoma that had the BRAF(V600E) mutation. Patients were randomized to receive either vemurafenib or dacarbazine. Co-primary end points were rates of overall and progression-free survival. Secondary end points included the response rate, response duration, and safety.

Patients receiving vemurafenib had a 74% reduction in the risk for progression (or death), compared with patients receiving dacarbazine. Mean progression-free survival was 5.3 months in the vemurafenib group, compared with 1.6 months in the dacarbazine group. At 6 months, estimated overall survival was 84% in the vemurafenib group and 64% in the dacarbazine group. The median survival of patients receiving vemurafenib has not been reached, while the median survival for those who received dacarbazine was 8 months.

Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse effects in patients receiving vemurafenib were joint pain, rash, hair loss, fatigue, nausea, and skin sensitivity to the sun. Approximately 26% of patients developed cutaneous squamous cell carcinoma, which was managed with surgery. Patients treated with vemurafenib should avoid sun exposure.

FDA approval of the cobas 4800 BRAF V600 mutation test was also based on data from the BRIM-3 trial. Patient tumor samples were tested with the diagnostic in order to select patients for the trial.

The complete response rate seen with vemurafenib has been only 0.9%. The great majority of patients experience tumor regrowth due to drug resistance. As we have discussed in previous article on this blog (for example, our January 23, 2011 article), researchers are hard at work developing combination therapies designed to overcome this resistance. As discussed in our June 8, 2011 blog article, research aimed at developing such combination therapies was extensively discussed at the 2011 ASCO meeting. We have also outlined strategies for overcoming vemurafenib resistance via design of multitargeted combination therapies in our June 2011 book-length report, Multitargeted Therapies: Promiscuous Drugs and Combination Therapies.

2011 has brought good news to patients who have or may develop late-stage melanoma, their families and friends, and to physicians who treat these patients. When previously there had been no FDA approved therapies that can produce improved survival in patients with this deadly disease, now there are two. We hope that research aimed at designing combination therapies to overcome drug resistance will result in even greater ability to control this disease, and that new therapies for still intractable forms of cancer will emerge in the next several years.

Two recent research reports may point the way to developing more effective, personalized therapies for two deadly women’s cancers for which their are currently few treatment options–triple-negative breast cancer and ovarian cancer. The approach followed in both reports is to use gene expression analysis to stratify each of the two diseases into subtypes. Researchers can then use gene expression and order aspects of the biology of each subtype to design subtype-specific targeted therapies, whether single drugs or drug combinations. If the drugs (whether approved or experimental) already exist, they can be tested in clinical trials, stratified by subtype. If no appropriate drugs exist, researchers can discover the drugs based on subtype-appropriate drug targets.

Triple-negative (TN) breast cancer refers to breast cancers that are negative for expression of estrogen receptor (ER), progesterone receptor (PR), and HER2. [HER2 is the target of trastuzumab (Roche/Genentech’s Herceptin) and lapatinib (GlaxoSmithKline’s Tykerb/Tyverb)]. Lacking all three receptors, it cannot be treated with standard receptor-targeting breast cancer therapeutics (e.g., tamoxifen, aromatase inhibitors, trastuzumab) but must be treated with cytotoxic chemotherapy. TN breast cancer is generally more aggressive than other types of breast cancer, and even treatment with aggressive chemotherapy regimens typically results in early relapse and metastasis.

TN breast cancers constitute approximately 25 percent of breast cancers. They are diagnosed most often in younger women, those who have recently given birth, women with BRCA1 mutations, and African-American and Hispanic women.

There is a Triple Negative Breast Cancer Foundation, which was founded in 2006 in honor of a mother in her mid-thirties who died of the disease.

Ovarian cancer, the ninth most common cancer in women, caused nearly 14,000 deaths in the U.S. in 2010. In its earliest stages, its symptoms are usually very subtle and mimic other, less serious diseases. As a result, it is usually detected at later stages in which treatment is more difficult and gives poorer outcomes. The 2001 five-year survival rate was 47%, up from 38% in the mid-1970s. This compared to an overall survival rate for cancer of 68% in 2001, up from 50% in the mid-1970s.

Treatment usually involves surgery and chemotherapy, and sometimes radiotherapy. Surgery (preferably by a gynecological oncologist) may be sufficient for earlier-stage tumors that are well-differentiated and confined to the ovary. In this early-stage disease (which represents about 19% of women presenting with ovarian cancer), the five-year survival rate is 92.7%. However, about 75% of women presenting with ovarian cancer already have stage III or stage IV disease, in which the cancer has spread beyond the ovaries. Then the prognosis is much poorer, and the vast majority of patients will have a recurrence.

The triple-negative breast cancer study

The TN breast cancer study was carried out by researchers at the Vanderbilt-Ingram Cancer Center (Vanderbilt University, Nashville, TN), and published in the 1 July 2011 issue of the Journal of Clinical Investigation. In this study, the researchers analyzed gene expression profiles from 21 publicly available breast cancer data sets, and identified  587 cases of TN breast cancer (by non-expression of mRNAs that encode ER, PR, and HER2). Using cluster analysis, they identified six TN breast cancer subtypes:

• two basal-like subtypes (BL1 and BL2),
• an immunomodulatory (IM) subtype (i.e., expressing genes involved in immune cell processes)
• a mesenchymal (M) subtype
• a mesenchymal stem–like (MSL) subtype
• a luminal androgen receptor (LAR) subtype.

Using gene expression analysis, the researchers identified TN breast cancer model cell lines that were representative of each of these subtypes. On the basis of their analysis, the researchers predicted “driver” signaling pathways, and targeted them pharmacologically as a proof-of-principle that analysis of gene expression signatures of cancer subtypes can inform selection of therapies.

BL1 and BL2 subtypes had higher expression of genes involved in the cell cycle and response to DNA damage, and model cell lines preferentially responded to cisplatin. M and MSL subtypes were enriched for expression of genes involved in the epithelial-mesenchymal transition (EMT), and growth factor-related pathways in model cell lines responded to the PI3K/mTOR inhibitor BEZ235 (Novartis, now in Phase 1 and 2 for solid tumors) and to the ABL/SRC inhibitor dasatinib [Bristol-Myers Squibb’s Sprycel, currently approved for treatment of chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL), and under investigation for treatment of solid tumors). The LAR subtype was characterized by androgen receptor (AR) signaling, and included patients with decreased progression-free survival. LAR model cell lines were uniquely sensitive to the AR antagonist bicalutamide (AstraZeneca’s Casodex/Cosudex, currently approved for the treatment of prostate cancer and hirsutism, and under investigation for treatment of androgen receptor-positive, ER negative, PR negative breast cancer).

The researchers plan to use the TN breast cancer subtype-specific model cell lines for further molecular characterization, to identify new components of the “driver” signaling pathways for each subtype. These pathways can be targeted in further drug discovery efforts. The subtype-specific cell lines can also be used in preclinical studies with targeted agents, and in identification of subtype-specific biomarkers that can potentially be used in stratifying TN breast cancer patients so that they might be treated with the best agents for their disease.

The ovarian cancer study

The ovarian cancer study was carried out by the Cancer Genome Atlas Research Network [a consortium of academic researchers jointly funded and managed by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI)], and published in the 30 June 2011 issue of Nature. In this study, the researchers analyzed mRNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas, as well as the DNA sequences of exons from coding genes in 316 of these tumors. Serous adenocarcinoma is the most prevalent form of ovarian cancer, accounting for about 85 percent of all ovarian cancer deaths.

The researchers found that nearly all of the high-grade serous ovarian cancers (HGS-OvCa) studied had mutations in the TP53 gene, which encodes the p53 tumor suppressor protein. On the basis of their gene expression (mRNA) signatures, the researchers divided the population of HGS-OvCa into four subtypes:

• an immunoreactive subtype (i.e., expressing genes involved in immune cell processes)
• a differentiated subtype (high expression of markers of differentiated female reproductive tract epithelia)
• a proliferative subtype (high expression of markers of cell proliferation)
• a mesenchymal subtype (high expression of HOX genes and of markers of mesenchymal-derived cells)

The researchers also determined subtypes on the basis of microRNA expression and promoter methylation. microRNA subtype 1 overlapped the mRNA proliferative subtype and miRNA subtype 2 overlapped the mRNA mesenchymal subtype. Patients with miRNA subtype 1 tumors survived significantly longer that those with tumors of other microRNA subtypes.

Although the researchers found no significant difference in survival between the four transcriptional subtypes, they did identify a 193-gene expression signature that was predictive of overall survival. 108 genes were correlated with poor survival and 85 were correlated with good survival.

The researchers identified cancer-associated pathways in the HGS-OvCA population; this is equivalent to the prediction of “driver” signaling pathways in the TN breast cancer study. They found that 20% of the HGS-OvCA samples had germline or somatic mutations in BRCA1 or BRCA2, and that 11% lost BRCA1 expression through DNA hypermethylation. As we discussed in an earlier article on this blog, BRCA1- or BRCA2-negative tumor cells cannot repair their DNA via homologous recombination. They are dependent on an alternative pathway of DNA repair, which involves the enzyme poly(ADP) ribose polymerase (PARP). These tumors are thus sensitive to a class of drugs known as PARP inhibitors, such as KuDOS/AstraZenaca’s olaparib. There are now six PARP inhibitors, including olaparib, in clinical development.

The researchers found genetic alterations in several other genes involved in homologous recombination. Altogether, defects in homologous recombination may be present in approximately half of HGS-OvCa cases, and these tumors may be sensitive to PARP inhibitors. This provides a rationale for clinical trials of PARP inhibitors in women with ovarian cancers with defects in homologous recombination-related genes.

Olaparib and other PARP inhibitors are in clinical trials in women with advanced with BRCA-1 or -2 mutations and with other defects in homologous recombination. As discussed in the 2011 ASCO meeting, early Phase 2 results indicate that olaparib gives dramatic improvements in progression-free survival in these women. (See this article.) In these studies, in addition to tumors with genetic defects in homologous recombination, olaparib or another PARP inhibitor, Abbott’s ABT-888, appears to give improved progression-free survival in women who have previously been treated with chemotherapy drugs that result in DNA damage. This suggests that oncologists may be able to use a “one-two punch”, consisting of a DNA-damaging drug [such as the alkylating agent temozolomide [Merck’s Temodar]) followed by a PARP inhibitor, to treat advanced ovarian cancer.

In addition to BRCA-1 and BRCA-2 mutations and other genetic alterations that result in defects in homologous recombination, the HGS-OvCa population exhibited genetic changes that would result in deregulation of several other cancer related pathways. These pathways included the RB1 (67% of cases), RAS/PI3K (45% of cases), and NOTCH (22% of cases) pathways, as well as the FOXM1 transcription factor network (87% of cases). All of these pathways represent opportunities for target identification and drug discovery. FOXM1 (Forkhead box protein M1) was named the Molecule of the Year for 2010 by the International Society for Molecular and Cell Biology and Biotechnology Protocols and Research (ISMCBBPR) because of “its growing potential as a target for cancer therapies.” FOXM1 overexpression results in destabilization of the cell cycle, which can lead to a malignant phenotype.

The researchers also identified 22 genes that were frequently amplified or overexpressed in HGS-OvCA tumors (other than genes that are involved in homologous recombination). Inhibitors (including approved and experimental compounds) already exist for the products of these genes, and researchers might assess these compounds in HGS-OvCa cases in which target genes are amplified.

Can Verastem develop new therapeutics for triple negative breast cancer?

The private biotechnology company Verastem (Cambridge, MA) focuses on discovery and development of drugs to target cancer stem cells. The company was founded in 2010, and is based on a strategy for screening for compounds that specifically target cancer stem cells. This strategy, published in the journal Cell in 2009, was developed by Drs. Robert Weinberg (MIT Whtehead Institute), Eric Lander (Broad Institute of MIT and Harvard University), and Piyush Gupta (MIT and Broad Institute) and their colleagues. Drs. Weinberg, Lander, and Gupta are on the Scientific Advisory Board of Verastem.

On July 14, 2011, Verstem announced that it had raised $32 million in a Series B financing. Verastem had previously raised $16 million from a group led by former Christoph Westphal’s Longwood Founders Fund. Dr. Westphal (formerly of Sirtris) is now Chairman of Verastem.

Cancer stem cells are best known in acute myeloid leukemia (AML), but their existence in other cancers (especially solid tumors) is controversial. The cancer stem cell hypothesis asserts that a small subpopulations of cells in a leukemia or solid tumor have characteristics that resemble normal adult stem cells, such as self renewal, the ability to give rise to all the cell types found in the leukemia or cancer, and stem cell markers. The hypothesis further asserts that most cancer treatments fail to knock out cancer stem cells, which can repopulate a tumor cell population, resulting in treatment relapses. Cancer stem cell researchers therefore propose developing cancer stem-cell specific therapeutics that can be used to eliminate these cells, which can block these relapses.

Whether cancer stem cells are involved in the pathobiology of solid tumors or not, the biology of the putative cancer stem cell phenotype can be important in certain subtypes of cancer. Cancer stem cells are characterized by the epithelial-mesenchymal transition (EMT), and in the Cell paper the researchers screened for compounds that specifically targeted breast cancer cells that had been experimentally induced into an EMT, and which as a result exhibited an increased resistance to standard chemotherapy drugs.   They identified the compound salinomycin as a drug that specifically targeted these cells, as well as putative cancer stem cells from patients.

As discussed earlier in this article, TN breast cancer includes two subtypes that have gene expression signatures related to the EMT: the mesenchymal (M) subtype and the mesenchymal stem–like (MSL) subtype. One or both of these subtypes might be sensitive to compounds that specifically target putative breast cancer stem cells. This may be true whether the cancer stem cell hypothesis applies to TN breast cancer or not. Verastem recognizes this, and is thus focusing on TN breast cancer as its first therapeutic target. The Vanderbilt TN breast cancer study suggests that trials of any “cancer stem cell-specific” therapeutics for TN breast cancer should be guided by subtype-specific biomarkers.

Hope for treatment of TN breast cancer and advanced ovarian cancer

Researchers and oncologists have made great strides in increasing the percentage of breast cancers that are treatable or even curable in recent years. For example, prior to the FDA approval of trastuzumab in 1998, HER2 positive breast cancer carried a grim prognosis. But the advent of trastuzumab (and later, lapatinib) has had a major impact on treatment of this once uniformly deadly type of breast cancer.

We hope that the new, personalized medicine-based approach to TN breast cancer and advanced serous ovarian adenocarcinoma will also result in successful new therapeutic strategies for these deadly women’s cancers.

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As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.

PLX4032

On January 19, 2011, Plexxikon and Roche announced the results of an interim analysis of a large multicenter Phase 3 clinical study (the BRIM3 trial) of the targeted anticancer drug PLX4032 (which Roche has designated as RG7204). PLX4032 is a kinase inhibitor that is exquisitely specific for B-Raf carrying the V600E mutation [B-Raf(V600E)]. This is the most common somatic mutation found in human melanomas (accounting for approximately 50% of cases of this disease), and is a “driver mutation” that is particularly critical for the malignant phenotype of human metastatic melanomas that carry the mutation.

According to the Plexxikon and Roche press releases, the Phase 3 trial met its prespecified criteria for co-primary endpoints of overall survival and progression-free survival, as compared to a control arm, in which patients were treated with the current standard of care, dacarbazine. The safety profile was consistent with previous clinical studies of the drug.

Based on the results of the interim analysis, patients in the dacarbazine arm of the study will have the option to crossover to receive PLX4032. Moreover, the Expanded Access Program will be opened to previously untreated melanoma patients whose tumors carry the B-Raf(V600E) mutation. As the companies announced in November 2010, as the result of widespread demand from patients, oncologists, and patient advocates, they had been in discussion with global regulatory authorities regarding an Expanded Access Program for PLX4032. In late December 2010, the Expanded Access Program for PLX4032 was initiated. A cofounder of one of the patient advocate organizations pushing for expanded access to PLX4032 prior to its FDA approval, the Abigail Alliance, commented on this issue on our blog in November 2010.

The big news in Plexxikon and Roche’s report on the BRIM3 trial is that treatment with PLX4032 gave enhanced overall survival as companied with dacarbazine in previously untreated metastatic melanoma patients carrying the B-Raf(V600E) mutation. Although previous studies showed tumor shrinkage and enhanced progression-free survival (by approximately seven months) in the majority of PLX4032-treated patients as compared to dacarbazine, this is the first report that PLX4032 give enhanced overall survival. However, the companies did not report the extend of the enhanced overall survival. They plan to present comprehensive data from the BRIM3 trial at a major scientific meeting later this year. We expect that in due course the researchers that have been conducting the trial will publish the results in a peer-reviewed medical journal, as in the case of the published Phase 1 trial.

On November 8, 2010, Plexxikon and Roche reported preliminary results of a parallel open-label Phase 2 trial (designated BRIM2) of PLX4032 in previously treated metastatic melanoma patients whose tumors carried the B-Raf(V600E) mutation. Researchers who had been conducting that trial presented the data at the Seventh Annual International Melanoma Research Congress of the Society for Melanoma Research (SMR) in Sydney, Australia. Consistent with earlier Phase 1 trials, the BRIM2 trial showed that of the 132 patients enrolled, 3 patients had complete responses, and 66 had partial responses (i.e., tumor shrinkage of over 30 percent). The overall response rate was 52 percent, with a median duration of response of 6.8 months. At the time the results were reported, it was too early to gauge overall survival.

The Biopharmconsortium Blog has been following the PLX4032 story since March 2010. We have published several articles on the drug and on related scientific, clinical trial strategy, and business issues:

https://biopharmconsortium.com/blog/2010/03/02/bringing-targeted-therapy-of-metastatic-melanoma-into-the-clinic-the-crucial-role-of-translational-researchers/

https://biopharmconsortium.com/blog/2010/03/10/plexxikon’s-discovery-of-plx4032-a-selective-targeted-therapeutic-for-metastatic-melanoma/

https://biopharmconsortium.com/blog/2010/08/27/phase-i-trial-of-plx4032-a-selective-therapeutic-for-metastatic-melanoma-published-in-nejm/

https://biopharmconsortium.com/blog/2010/10/13/translational-research-in-cancer-makes-a-big-splash-in-nature-part-1/

https://biopharmconsortium.com/blog/2010/10/25/translational-research-in-cancer-makes-a-big-splash-in-nature-part-2/

The last two articles discuss the novel personalized medicine (or “stratified medicine”) hypothesis-testing clinical trial strategy, which is especially applicable to highly targeted oncology drugs (such as PLX4032) for which the relevant biomarkers are available.

The dramatic results of the Phase 1 trials of PLX4032 (now confirmed by Phase 2 and Phase 3 trials) led some oncologists, as well as patient advocates, to question the ethics of conducting standard controlled Phase 3 trials in which some patients were placed in a dacarbazine arm.  This question might apply to other drugs for cancer and other very serious diseases for which personalized medicine hypothesis-testing clinical trials indicate superior performance as compared to the standard of care. Such cases would at least call for establishment of  Expanded Access Programs for such drugs, on a case-by-case basis.

The clinical trial community, as well as regulatory agencies such as the FDA and the European Medicines Agency, also need to continue to monitor and study the progress of the personalized medicine hypothesis-testing clinical trial strategy. This may led to modifications in clinical trial standards for approval if they deem they are warranted. We can also expect that patient advocates (including M.D. and non-physician advocates), as well as other stakeholders (e.g., third party payers) would be participating in that process.

In parallel with the development of PLX4032, Plexxikon and Roche Molecular Diagnostics are developing a DNA-based companion diagnostic to identify patients whose tumors carry B-Raf(V600E). The companies plan to launch PLX4032 together with the companion diagnostic, so that oncologists can readily identify patients who would benefit from treatment with the drug.

Despite the dramatic results with PLX4032, so far all patients treated with the drug eventually suffer relapses, and die of their disease. This presumably occurs because a fraction of tuner cells develop resistance to PLX4032. Oncologists, especially those who have been involved in the clinical trials of the drug, therefore advocate using PLX4032 as the basis for potentially still more effective treatments, especially combination therapies.

With respect to combination therapies, on January 6, 2011, Plexxikon announced that it had signed an agreement with Genentech (a member of the Roche group) to co-promote PLX4032 (RG7204) in the United States. Plexxikon will also codevelop PLX4032 with Genentech in addition to Roche. Plexxikon and Genentech are planning, beginning in the first quarter of 2011, to begin a Phase 1b clinical trial of a combination therapy of PLX4032 and Exelixis/Genentech’s oral, small-molecule MEK inhibitor RG7420/GDC-0973. MEK is downstream from B-Raf in the signaling pathway by which B-Raf(V600E) acts to produce the malignant phenotype. Researchers studying mechanisms by which PLX4032 resistance occurs have found evidence that suggests that combination therapy with PLX4032 and a MEK inhibitor may overcome resistance that occurs via some mechanisms. More generally, studies of mechanisms of PLX4032 resistance may provide means of developing specific combination therapies for different mechanisms of resistance, and of stratifying patients to determine which particular personalized combination therapy will best treat their disease.

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As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.

Olaparib

In Part 1 of this series, we began a discussion of a new, disruptive strategy for clinical trials of oncology drugs, which had been outlined in a Perspective by Drs. Johann S. de Bono and Alan Ashworth, and published in the 30 September 2010 issue of Nature.

This strategy, which these authors call the personalized medicine hypothesis-testing strategy, is aimed at testing targeted drugs that have been developed via biology-driven drug discovery. Such a strategy begins with a strong biological hypothesis that a particular altered molecular target is critical for the malignant phenotype of a particular cancer. Based on this hypothesis, drug discovery researchers develop both targeted drugs that are specific for these altered targets, and biomarkers that can be used to determine which patients have tumors that express the target, and thus are most likely to benefit from treatment with the drug.

Following preclinical studies, clinical researchers test the drug in patients whose tumors express the target, aiming for proof of mechanism and proof of concept in early clinical trials. This involves the use of rapid dose escalation and adaptive trial design. Following these early trials, the researchers go on to conduct Phase 3 clinical trials, aiming at registration. This strategy is designed to reduce clinical attrition and the time and cost of clinical trials, and to develop superior, targeted drugs that provide greater patient benefit (in terms of progression-free survival) than the typical new oncology drugs that reach the market.

In the de Bono and Ashworth article, the authors provide several examples of successful hypothesis-testing clinical trials using this strategy. In this blog post, we discuss three of these examples, one of which is a “classic” that should be familiar to most of you, another which we have discussed in previous articles on this blog, and a third example that is based on Drs. de Bono and Ashworth’s own research.

Imatinib (Novartis’ Gleevec/Glivec)

The “classic” example of the use of a personalized medicine hypothesis-testing strategy is the development of imatinib (Novartis’ Gleevec/Glivec).  This drug was originally designed as a specific inhibitor of the ABL tyrosine kinase, which is stuck in the activated conformation in the BCR-ABL fusion protein. BCR-ABL is the “driver” mutation in Philadelphia chromosome-positive chronic myeloid leukemia (CML). Imatinib was also found to be specific for two other tyrosine kinases, c-Kit and the platelet-derived growth factor receptor (PDGFR); these findings have led to the use of imatinib to treat other cancers, especially gastrointestinal stromal tumors (GIST). We discussed the role of Dr. Brian Druker (Oregon Health Sciences University in Portland) and Nicholas B. Lydon (then at Novartis) in the development of imatinib in an earlier blog post.

The 2001 published Phase 1 clinical trial of imatinib in CML led by Drs. Druker and Lydon, and clinician Charles L Sawyers, M.D. (Memorial Sloan-Kettering Cancer Center/Howard Hughes Medical Institute) is what Drs. de Bono and Ashworth called “a landmark paper” in the use of a personalized medicine hypothesis-testing strategy to demonstrate the efficacy and safety of a targeted oncology drug. The development of imatinib for CML was made possible by basic research that showed that the BCR-ABL fusion protein (which is generated as the result of the translocation that produces the Philadelphia (Ph) chromosome, the characteristic genetic abnormality of CML) alone was sufficient to cause CML, and that the tyrosine kinase activity of the ABL moiety of the protein was required for its oncogenic activity. Researchers then discovered a compound, imatinib, that was highly specific for BCR-ABL, c-kit, and PDGFR.

The Phase I clinical trial (which took place in 1999) was a dose-escalation trial of imatinib in 83 patients with chronic-phase CML in whom treatment with interferon-alpha had failed. The primary endpoint of the trial was the safety and tolerability of the drug; efficacy was a secondary endpoint. Imatinib was found to be well-tolerated, and a maximum tolerated dose was not identified in this trial. Complete hematological responses (defined by reductions in the white-cell and platelet counts) were seen in 53 of 54 patients who received 300 mg per day or more of imatinib; these responses typically occurred in the first four weeks after initiating treatment. Cytogenetic responses were defined by the percentage of blood cells in metaphase that were positive for the Ph chromosome, ranging from major responses (zero to 35% of Ph chromosome-positive cells) to minor responses (36-65% positive) to no response (over 65% positive). Of the 54 patients treated with doses of 300 mg or more, 29 had cytogentic responses, including 17 with major responses; seven of these patients had complete cytogenetic remissions (durable zero percent Ph chromosome positive).

Blood samples were taken to determine whether BCR-ABL tyrosine kinase activity had been inhibited by in vivo treatment with imatinib. The researchers observed dose-dependent inhibition of BCR-ABL tyrosine kinase activity. This constituted proof of mechanism of the drug, while the antileukemic activity of imatinib in the trial constituted proof-of-concept.

The researchers then conducted Phase 2 clinical trials, which confirmed and extended the results seen in Phase 1. The FDA approved imatinib in May 2001, less than three years after initiation of clinical trials. This rapid approval was made possible by the FDA granting imatinib a Fast Track designation and Accelerated Approval, which allowed approval of the drug based on Phase 2 trials using surrogate markers (in this case, cytogenetic responses).

As imatinib gained approval as frontline therapy for treatment of Ph chromosome-positive CML, resistance to imatinib became an important issue. Researchers found that this resistance was usually due to mutations in BCR-ABL that interfere with imatinib binding. Two companies therefore designed inhibitors that can bind to and inhibit these resistant BCR-ABL proteins and thus successfully treat imatinib-resistant CML–dasatinib (Bristol-Myers Squibb’s Sprycel) and nilotinib (Novartis’ Tasigna). This is an example of the use of reiterative translational studies to determine mechanisms of drug resistance, and the design of second-generation drugs to combat this resistance. This type of follow-up strategy was discussed in the de Bono and Ashworth article and in our previous blog post.

Only a few years ago, many industry commentators were of the opinion that the development of imatinib to treat CML was a unique case, and development of other personalized biology-driven drug discovery-based cancer medicines would not be successful. However, the examples discussed in the de Bono and Ashworth article (and elsewhere) show that that is not true.

Roche/Plexxikon’s PLX4032

The second example of successful use of the hypothesis-testing clinical trial strategy is the development of Roche/Plexxikon’s PLX4032 for metastatic melanoma. This compound is exquisitely specific for B-Raf carrying the V600E mutation B-Raf(V600E). This is the most common somatic mutation found in human melanomas, and is a “driver mutation” that is particularly critical for the malignant phenotype of human metastatic melanomas that carry the mutation.

We have discussed PLX4032 in three articles on this blog in 2010, published on March 2, March 10, and August 27.

As in the case of imatinib, researchers achieved proof-of-mechanism and proof-of-concept for PLX4032 in a dose-escalation Phase 1 trial in patients who were preselected for carriers of the B-Raf(V600E) mutation. The Phase 1 trial took place in 2008/2009. This was followed by an extension phase in which patients were given the maximum tolerated dose of the drug. Patients showed an 81% response rate (i.e, a partial or a complete response). The estimated median progression-free survival among all patients was over 7 months, as compared to less than 2 months in large numbers of advanced melanoma patients as determined by historical analysis. Oncologists had never seen such a dramatic response in treatment of metastatic melanoma.

PLX4032 is on an accelerated path to potential registration, and parallel Phase 2 and Phase 3 clinical trials are in progress in previously treated and previously untreated patients, respectively, all who have metastatic melanoma carrying the B-Raf(V600E) mutation.

Despite the dramatic regressions and increased survival seen in the Phase 1 trials, all the patients apparently eventually suffered relapses. As stated in the article on PLX4032 in the 30 September 2010 issue of Nature, researchers are therefore doing reiterative translational studies to determine the mechanisms of resistance to PLX4032 in cases of tumor regrowth after treatment with the drug. Proposed strategies include the development of combination therapies that include PLX4032 and other targeted drugs, immunotherapeutic agents, or chemotherapy. Given the promising efficacy and safety profile of PLX4032, researchers believe that the drug has the potential to enable the development of such combination therapies.

In conjunction with the early clinical trials of PLX4032, researchers developed a real-time polymerase chain reaction (PCR) assay to assess B-Raf(V600E) mutation status. The assay has the potential to be used as a companion diagnostic in treatment with PLX4032.  As stated in the 30 September article, researchers are assessing the reliability of the PCR assay In the ongoing concurrent Phase 2 and Phase 3 clinical trials of PLX4032.

A synthetic lethal therapeutic strategy using KuDOS/AstraZeneca’s olaparib

The third example of successful use of the hypothesis-testing clinical trial strategy is taken from Drs. de Bono and Ashworth’s own work. The therapeutic strategy in this example is fundamentally different from the cases of imatinib and PLX4032, both of which are exquisitely targeted drugs that inhibit specific mutated versions of oncogenes. Instead, this example involves the use of synthetic lethality in the design of an anticancer therapeutic strategy. Based on classic studies in yeast and Drosophila, synthetic lethality is defined as a situation in which mutation in either of two genes individually has no effect, but simultaneous mutation in both genes is lethal. In cancer, if one gene in a synthetically lethal pair is defective (and especially if this defect is involved in the malignant phenotype) targeting the other gene with a drug should be selectively lethal to the tumor cells but not to normal cells. If this works, it should result in a large therapeutic window for treatment with the drug.

Women with a germline mutation in one BRCA1 or BRCA2 allele have a high risk of developing breast and ovarian cancer; BRCA1 or BRCA2 carrier status in men also carries an increased risk of developing prostate cancer. Via the process of loss of heterozygosity, cells of carriers of loss-of-function mutations in BRCA1 or BRCA2 can lose the wild-type allele, resulting in cells that lack BRCA1 or BRCA2 function. The products of the two BRCA genes are both involved in the pathway for DNA repair via homologous recombination. Loss of a functional homologous recombination pathway results in the development of genomic instability that can lead to carcinogenesis. Moreover, since BRCA-negative tumor cells cannot repair their DNA via homologous recombination, they are dependent on an alternative pathway of DNA repair, which involves the enzyme Poly(ADP) ribose polymerase (PARP). Since the average cell must repair its DNA thousands of times a day, researchers hypothesized that BRCA-negative tumor cells should be uniquely vulnerable to drugs that inhibit PARP. In contrast, normal cells are able to utilize the homologous recombination pathway, and should not be affected by PARP inhibitors.

Alan Ashworth and his colleagues developed and published this synthetic lethality strategy for therapy of BRCA-negative breast cancer in 2005. They showed that cells deficient in BRCA1 or BRCA2 were about 1,000-fold more sensitive to a class of PARP inhibitors developed by AstraZeneca (AZ) subsidiary KoDOS Pharmaceuticals (Cambridge, MA) than cells with BRCA1 and BRCA2 function. Treatment of BRCA-deficient cells with the PARP inhibitors resulted in chromosomal instability and cell cycle arrest, followed by apoptosis. The efficacy and specificity of the PARP inhibitors for BRCA-deficient cells also carried over to in vivo studies in mouse models. These cell culture and animal studies constituted the generation of a strong hypothesis that this synthetic lethal therapeutic strategy would be useful in developing antitumor treatments for patients with BRCA-negative breast cancer.

In 2006 and 2007, Drs. Ashworth, de Bono, and their colleagues (including researchers from KuDOS and AZ) conducted a Phase 1, hypothesis-testing clinical trial of KuDOS/AZ’s potent, orally-active PARP inhibitor olaparib (AZD-2281; formerly known as KU-0059436). The study enrolled a total of 60 patients with a variety of types of solid tumors, including 22 who were confirmed BRCA1 or BRCA2 mutation carriers and one patient with a strong family history of BRCA-associated cancer but who declined mutation testing. The study was published in July 2009 in the New England Journal of Medicine. The trial was a dose-escalation study–the dose was increased from 10 mg daily for two of every three weeks to 600 mg twice daily. A reversible dose-limiting toxicity was seen in one of eight patients receiving 400 mg twice daily, and in two of five patients who received 400 mg twice daily. Based on these results, the researchers established 400 mg twice daily as the maximum tolerated dose. They then enrolled a new cohort of carriers of a BRCA1 or BRCA2 mutation; these patients received a dose of 200 mg twice daily.

As a Phase 1 trial, the primary objectives were to determine safety, adverse effects, the dose-limiting toxicity and maximum tolerated dose, and the pharmacokinetic and pharmacodynamic profiles. Once these were established, the aim was to test the hypothesis that patients’ BRCA1 or BRCA2 mutation-associated cancers would show an objective antitumor response to olaparib as a single agent. In terms of safety, adverse effects were generally mild. There were two patients deaths due to infectious disease that were deemed not to be drug related. There was also no difference in adverse effect profiles between known BRCA1 and BRCA2 mutation carriers and other patients.

The researchers established three types of biomarkers. The predictive biomarker was the presence of BRCA1 or BRCA2 loss-of-function mutations, as determined by standard sequencing methods in patients with a family history of BRCA-associated cancers. The pharmacodynamic biomarker was the inhibition of PARP enzymatic activity in peripheral blood mononuclear cells and in tumor biopsies taken before and after olaparib treatment, and the formation of double-strand DNA breaks in hair follicle tissue. The intermediate endpoint biomarker consisted of radiological determination of tumor shrinkage and biochemical tests for serum tumor markers.

Using the pharmacodynamic biomarker, the researchers showed that inhibition of PARP was over 90% in peripheral mononuclear cells in patients treated with 60 mg or more of olaparib twice daily. Determination of PARP activity in tumor biopsies before and after 8 days of treatment showed that drug treatment inhibited PARP in tumor tissue. Pharmacodynamic studies in samples of plucked eyebrow hair follicles showed that induction of formation of double-strand breaks occurred within 6 hours of olaparib treatment. These studies constitute proof-of-mechanism of olaparib in humans.

In studies to determine whether olaparib treatment induced antitumor responses, the researchers found that such responses only occurred in patients with confirmed BRCA1 or BRCA2 mutation carrier status, except for one patient who declined mutational testing but had a strong family history of BRCA mutation-related cancer. 23 patents who were confirmed or (in the one case) deemed to be BRCA mutation carriers were treated. Of these 23 patients, two could not be evaluated. Two of the remaining patients had tumors not typically associated with BRCA mutations, and neither received clinical benefits from drug treatment.

Of the remaining 19 patients (who had ovarian, breast, or prostate cancer), 12 exhibited clinical benefits from olaparib treatment, with either tumor responses (determined radiologically or via serum tumor markers) or stable disease for a period of four months or more. Nine BRCA carriers had a tumor response. Eight patients with advanced ovarian cancer had a partial response (determined by radiology), and six of these had a greater than 50% tumor response based on tumor marker assays. Of the three patients with advanced BRCA2 breast cancer, one had a complete remission lasting for over 60 weeks, and another had stable disease for 7 months. The other breast cancer patient, who had refused mutational testing, had a decline in metastases and an over 50% decline in serum tumor markers. The patient with BRCA2-related castration resistant prostate cancer has an over 50% reduction in PSA levels, and resolution of bone metastases. He had been participating in the study for over 58 weeks at the time of the cutoff date, and for more than 2 years since that date.

The above efficacy data constitutes proof-of-concept, and confirms the hypothesis that BRCA-associated cancers can be addressed by a synthetic lethal therapeutic strategy based on the use of the PARP inhibitor olaparib. Olaparib also has a satisfactory adverse effect profile, and lacks the toxicity typically seen with cancer chemotherapy. Since this Phase 1 clonal trial, AZ had taken olaparib into Phase 2 clinical trials in advanced BRCA-related breast and ovarian cancer. Olaparib has continued to demonstrate efficacy and a relatively mild adverse effect profile in these trials, as shown here and here, and as also discussed in a July 2010 Medscape article.

Dr. Ashworth and his colleagues noted that not all cancers in BRCA1 or BRCA2 carriers respond to olaparib. They hypothesize that different BRCA1 or BRCA2 mutations may result in different defects in homologous recombination, which may cause variations in sensitivity to PARP inhibition. Moreover, certain secondary BRCA2 mutations may restore BRCA function, which may cause resistance to PARP inhibition. They see the need to develop assays for homologous recombination proficiency, which might be used in reiterative translational studies to determine causes of resistance to olaparib.

Synthetic lethal therapy with PARP inhibitors such as olaparib may be applicable to other types of cancers that have defects in DNA repair by homologous recombination. These may include sporadic breast and ovarian cancers that acquire loss of function of BRCA1 or BRCA2 via somatic genetic or epigenetic events, and other sporadic cancers that develop loss of function (via somatic genetic or epigenetic events) of other proteins involved in the homologous recombination DNA repair pathway.

Dr. Ashworth and his colleagues have also shown that loss of function of DNA damage signaling proteins (e.g., ATM, ATR, CHK1, CHK2), and of Fanconi anemia proteins, can induce sensitivity to PARP inhibition. Loss of function in these pathways may be relatively common in other sporadic cancers. It will be essential to develop biomarkers for loss of function of these DNA repair proteins in order to design hypothesis-testing clinical trials to investigate the potential of olaparib (or other PARP inhibitors) to treat this broader class of cancers.

As show by these three examples–and the other examples discussed in the 30 September 2010 de Bono and Ashworth Perspective (see Box 5 in that article)–researchers have been using the personalized medicine hypothesis-testing strategy to develop exciting new oncology drugs to treat disease in specific classes of patients. However, except for the case of imatinib, all of the drugs are still in clinical trials and have not yet achieved registration, which is the real test of the success of this strategy. Moreover, as we discussed in the first article in this series, the personalized medicine hypothesis-testing strategy is a work in progress. For example, biomarker identification and qualification/validation, which is a critical need for further development and utilization of this new clinical trial strategy, is an early-stage area of science and technology. Nevertheless, the personalized medicine hypothesis-testing strategy for cancer drug development provides a means to extend biology-driven drug discovery into the clinic, to decrease the time and cost of clinical trials, and to develop anticancer drugs that should be superior to both conventional chemotherapy and to early-generation targeted drugs.

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As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please contact us. We also welcome your comments on this or any other article on this blog.