In our last blog post (April 15, 2010), we discussed genetically engineered mouse cancer models, with emphasis on the work of Dr. Pier Paolo Pandolfi (Beth Israel-Deaconess Medical Center Cancer Center and the Dana-Farber/Harvard Cancer Center, Boston MA) and his colleagues. Part of that discussion was on Dr. Pandolfi’s earlier work on the construction of genetically engineered models of acute promyelocytic leukemia (APL), and the use of these models in designing therapies for that disease. As the result of these studies and the work of others, the major form of APL (in which leukemic cells express the fusion protein PML-RARα) is now treated with a combination of all-trans retinoic acid (ATRA) and arsenic trioxide (As₂O₃). What once was an invariably fatal disease now has about a 90% survival rate.

For those of you who are interested in the mechanisms by which ATRA and As₂O₃ work in treatment of APL: the 9 April 2010 issue of Science has a Perspective and a research report that focus on the mechanistic basis for the action of As₂O₃. For the mechanistic basis of the action of ATRA in APL, you may read a November 2008 research report published in Nature Medicine.

As soon as I posted the blog article on Dr. Pandolfi’s work, I received my 9 April issue of Science with the articles on As₂O₃ in APL. So I am passing this information on to readers of this blog.

The April 1, 2010 issue of The Scientist has an article, entitled “Building a better mouse”, on efforts of researchers to develop improved mouse models of cancer.

Current mouse models of cancer, mainly xenograft models in which human cancer cell lines are transplanted into immune deficient mice, are notoriously unpredictive of efficacy when oncology drug candidates are tested in them. This is a major factor in the high failure rate of oncology drugs in clinical trials. It is estimated that oncology drugs that enter human clinical trials have a 95 percent attrition rate, as compared to the 89 percent attrition rate for all clinical candidates. (Poorly predictive animal models are a major factor in the failure of clinical candidates in all therapeutic areas, but cancer models are particularly unpredictive.)

The Scientist article focuses on the ongoing “co-clinical mouse/human trials” now being led by Pier Paolo Pandolfi, MD, PhD (Director, Cancer and Genetics Program, Beth Israel-Deaconess Medical Center Cancer Center and the Dana-Farber/Harvard Cancer Center). Dr. Pandolfi and his colleagues have constructed genetically engineered transgenic mouse strains that have genetic changes that mimic those found in human cancers. These mouse models spontaneous develop cancers that resemble the corresponding human cancers. In the co-clinical mouse/human trials, researchers simultaneous treat a genetically engineered mouse model and patients with tumors that exhibit the same set of genetic changes with the same experimental targeted drugs. The goal is to determine to what extent the mouse models are predictive of patient response to therapeutic agents, and of tumor progression and survival. The studies may thus result in validated mouse models that are more predictive of drug efficacy than the currently standard xenograft models.

The human clinical trials being “shadowed” by simultaneous studies in mice include Phase III trials of several targeted therapies for lung and prostate cancer. Xenograft models in which tumor tissue from the patients have been transplanted into immunosuppressed mice are being tested in parallel with the genetically engineered mouse models. This two-year project represents the most rigorous test to date of how well genetically engineered mouse models of cancer can predict clinical outcomes.

Dr. Pandolfi started in the mouse cancer model field with his studies of acute promyelocytic leukemia (APL). Unlike humans, mice do not naturally develop APL. Chromosomal translocations, in which the gene for the retinoic acid receptor alpha (RARα) (located on chromosome 17) becomes fused to one of several partner genes (known as “X genes”) on different chromosomes, are involved in the causation of APL. In over 98% of cases of APL, RARα is fused to the promyelocytic leukemia (PML) gene, located on chromosome 15. In a relatively small percentage of cases, RARα is fused to other X genes. An example of one of these other genes is the promyelocytic leukemia zinc finger (PLZF) gene, located on chromosome 11.

In studies in the late 1990s, Dr. Pandolfi and his colleagues constructed transgenic mice that expressed either PML-RARα or PLZF-RARα transgenes, in a promyelocytic-specific manner. (Expression of these transgenes in every cell of a mouse embryo results in embryonic lethality, and their expression in all early hematopoietic progenitors results in impaired myelopoiesis but no leukemia; these transgenic mice are thus not informative with respect to APL. The researchers were able to model PML only by expressing the transgenes specifically and exclusively in promyelocytes.)

The promyelocytic-specific PML-RARα-transgenic mice exhibit abnormal hematopoiesis over their first year of life, and between 12-14 months of age 10% of them develop APL.The promyelocytic-specific PLZF-RARα transgenic mice also exhibit a long latency period, and a subset of these mice eventually develops a leukemia that has features of human chronic myelogenous leukemia (CML).

Importantly, the above transgenic mouse models were useful in designing therapies for human patients. The leukemias in both the PML-RARα-transgenic mice and in patients with the PML-RARα translocation were responsive to treatment with all-trans retinoic acid (ATRA) (Genentech’s Vesanoid, generics). However, both the PLZF-RARα transgenic mice and patients with APL bearing the PLZF-RARα translocation were not responsive to ATRA. APL patients who initially responded to ATRA developed resistance to the drug, as did the PML-RARα transgenic mice. Using the PML-RARα transgenic mice, the researchers found that a combination of ATRA with arsenic trioxide (As₂O₃) (Cephalon’s Trisenox) cured the mice of leukemia. This later proved to also be true for human patients with APL bearing the PML-RARα translocation. Thus a cancer that once was uniformly fatal now has an approximately 90% survival rate.

Leukemic mice with the PLZF-RARα transgene were not responsive to As₂O₃. However, later studies have indicated that histone deacetylase inhibitors such as phenylbutyrate, in combination with ATRA, may be effective in treating these transgenic mice. These drug combinations may therefore be effective in APL patients with the PLZF-RARα translocation.

The success of Dr. Pandolfi’s genetically engineered mouse model in designing an effective therapy for the major type of APL illustrates the potential power of improved mouse models for cancer. Of course, this is a special case, since researchers were able to use the model to design an effective therapy using already-approved drugs. In most cases, researchers use the models to develop novel therapeutic strategies for a particular cancer, which involves discovery and development of new drugs or design of clinical trials using experimental drugs that have yet to be approved. The “co-clinical mouse/human trials” being run by Dr. Pandolfi and his colleagues may result in additional validation of the power of genetically engineered mouse models of cancer, and may thus encourage their adoption by companies developing new oncology drugs.

Our recently published book-length report, Animal Models for Therapeutic Strategies, includes a case study on a genetically engineered model of pancreatic cancer. Pancreatic cancer is one of the most lethal of cancers. Although models bearing transplanted human pancreatic tumors (i.e., xenograft models) are sensitive to numerous chemotherapeutic agents, human pancreatic cancers are insensitive to the same agents. Using a genetically engineered mouse model of pancreatic cancer, researchers hypothesized that the reason for the insensitivity of human pancreatic cancer (and of tumors in the mouse model) is impaired drug delivery. Researchers have been using the mouse model to develop novel therapeutic strategies to enhance drug delivery and thus to achieve improved treatment of this disease.

Our 2009 book-length report, Approaches to Reducing Phase II Attrition, includes a case study on adoption of genetically engineered cancer models by industry. Most animal models designed to enable researchers to develop novel therapeutic strategies for complex human diseases are developed by academic researchers. This includes genetically engineered cancer mouse models. However, most drugs are developed by industry, not academia. Industrial researchers are hampered in their ability to develop successful new oncology drugs by the poorly predictive xenograft models. Genetically engineered mouse models of cancer may help biotechnology and pharmaceutical company researchers to be more productive in oncology drug development, provided the corporate researchers can adopt these animal models for use in their discovery research and preclinical studies. However, for several reasons, industry has not widely adopted these models.

Our report discusses the barriers to adoption of these models, large pharmaceutical companies that are beginning to adopt the models, and the biotechnology company Aveo Pharmaceuticals, whose technology platform is based on in-licensing genetically engineered mouse cancer models from its principals’ academic laboratories and developing new models in-house. Aveo uses its models in its own internal drug discovery and development, and also collaborates with several large pharmaceutical companies. Aveo thus serves as a means of technology transfer from academia to industry, including both to its own internal programs and to its partners. The article in The Scientist also discusses Aveo’s research on genetically engineered mouse cancer models, and their use in the company’s internal drug development programs.

In our March 2, 2010 blog post, we focused on a Phase I clinical trial of Plexxikon/Roche’s PLX4032, in which clinical researchers led by Keith T. Flaherty achieved a dramatic breakthrough in treatment of metastatic melanoma. Now we shall discuss the discovery of the drug itself, PLX4032.

In 2002, a research consortium based at the Wellcome Trust Sanger Institute in the U.K. found B-Raf somatic missense mutations in 66% of malignant melanomas (as well as in a subset of other cancers). V600E (valine substituted by glutamic acid at position 600) accounted for 80% of these mutant forms of B-Raf. The V600E mutation causes destabilization of the inactive conformation of B-Raf kinase, shifting the equilibrium toward the catalytically active conformation.

B-Raf is a serine/threonine protein kinase that is a component of an intracellular pathway that mediates signals from growth factors. B-Raf is regulated by binding to Ras. In turn, B-Raf activates MEK (mitogen-activated protein kinase kinase), which activates ERK (extracellular signal-regulated kinase). Activated ERK goes on to upregulate transcriptional pathways that promote cellular proliferation and survival.

Growth factors → →Ras→ B-Raf→ MEK→ ERK→ →upregulation of cell proliferation and survival

Growth factor signaling via Ras also controls other signaling pathways that upregulate cell proliferation, notably the PI3K-Akt (phosphatidylinositol-3-OH kinase-Akt) pathway.

The Sanger researchers found evidence that cells carrying B-Raf(V600E) no longer require Ras function for proliferation. This would mean that melanoma cells carrying this mutation could proliferate independently of growth factor signaling, resulting in the runaway proliferation characteristic of the malignant phenotype.

These results suggested that B-Raf(V600E) would be a good target for novel kinase inhibitors to treat malignant melanoma. The first such kinase inhibitors to be developed, although they had inhibitory activities at low nanomolar concentrations against B-Raf (both wild-type and mutant), were not successful in the clinic, due to their inhibition of multiple nonspecific targets and/or their poor bioavailability. Plexxikon researchers therefore set out to discover inhibitors that are highly selective for B-Raf(V600E). The result was the discovery of PLX4032.

The discovery of PLX4720 (a tool compound or chemical probe related to PLX4032) by Plexxikon researchers and their academic colleagues, and its preclinical validation, is described in a 2008 publication, Tsai et al. Plexxikon used its proprietary “scaffold-based drug design” technology platform to discover PLX4720. Scaffold-based drug design involves synthesizing sets of low-molecular weight “scaffold-like’” compounds. These compounds interact (typically at low affinity) with many members of a protein family by targeting their conserved regions.

In the B-Raf study, the researchers identified protein kinase scaffolds by screening a select library of 20,000 150-350-dalton compounds for inhibition of a set of three structurally characterized protein kinases at a concentration of 200 micromolar (μM). Of this library, 238 compounds were selected on the basis of their inhibition of the kinases by at least 30% at the 200 μM concentration. Each of the compounds was cocrystallized with one if the three kinases, Pim-1. Using this method, the researchers found that 7-azaindole bound to the ATP-binding site of Pim-1 kinase. They further modified this compound by adding side chains on the 3 position of 7-azaindole, resulting in a “scaffold candidate” with increased affinity for the ATP binding site of PIm-1 and other kinases. The researchers further modified this scaffold, based on structural data from other kinases. Ultimately, they cocrystallized their modified compounds with wild-type B-Raf and B-Raf(V600E), and optimized the structure of their compounds to give a compound, PLX4720, with selectivity for B-Raf(V600E) and against wild-type B-Raf and other kinases. This process (including the relevant chemical and protein structures) is illustrated in Figure 1 of Tsai et al.

In biochemical assays, the researchers found that PLX4720 inhibited B-Raf(V600E) at low nanomolar concentrations, and was 10-fold more selective for B-Raf(V600E) than for wild-type B-Raf, and was even more selective for B-Raf(V600E) than for other kinases.

Surprisingly, in cellular assays, PLX4720 is over 100-fold (not 10-fold) more selective in inhibiting proliferation of tumor cell lines that bear B-Raf(V600E) as compared to those that bear wild-type B-Raf. Moreover, as first found by researchers at Pfizer and their academic collaborators, a specific inhibitor of MEK (Pfizer’s CI-1040) is also similarly selective for tumor cell lines bearing B-Raf(V600E). This suggests that the B-Raf-MEK-ERK pathway is critical for the proliferation of B-Raf(V600E) cells, but not for cells bearing wild-type B-Raf. [For example, tumor cells that bear wild-type B-Raf might use the PI3K-Akt pathway to upregulate pathways that control cell proliferation independent of ERK signaling, while tumor cells that bear B-Raf(V600E) cannot.]

The B-Raf-MEK-ERK pathway dependence of B-Raf(V600E) cells may in part be related to feedback inhibition of B-Raf (and other isoforms of Raf). Activated ERK can phosporylate wild-type Raf isoforms at specific inhibitory sites. This results in downregulation of signaling via the Raf-MEK-ERK pathway. However, in cells bearing B-Raf(V600E), this feedback inhibition is disabled, resulting in uncontrolled signaling.

The Plexxikon researchers (Tsai et al.) tested PLX4720 against tumor xenograft models. Oral administration of PLX4720 blocked tumor growth, and in 4 out of 9 cases caused tumor regressions, in mice with tumor xenografts bearing B-Raf(V600E). Treatment with PLX4720 was well tolerated, and showed no adverse effects. Growth of tumor xenografts bearing wild-type B-Raf was not affected by PLX4720. In mice with tumors bearing B-Raf(V600E), PLX4720 blocked B-Raf-MEK-ERK pathway signaling, as demonstrated by immunohistochemical assays.

The exquisite specificity of PLX4720/PLX4032 for B-Raf(V600E) as compared to wild-type B-Raf was made possible by Plexxikon’s structure-guided “scaffold-based drug design” technology. Other structure-guided drug design technologies, such as fragment-based lead design, as is carried out in several companies, might be used to design comparably specific drugs.

The discovery of PLX4720/PLX4032 is an example of the use of new-generation chemistry technologies (or the revival of the old, and now disused natural products chemistry approach), coupled with biology-driven drug discovery strategies, to discover promising new drugs. We have discussed this strategy in several articles on this blog. (For example, see here and here).

Despite the promising results seen in Phase I clinical trials of PLX4032, it must be emphasized that the establishment of the efficacy and safety of this compound awaits the completion of the ongoing Phase III trials. Moreover, despite the dramatic regressions and increased survival seen in the Phase I trials, all the patients apparently eventually suffered relapses. Dr. Flaherty, as discussed in our earlier blog post, sees the need for combination therapies to effectively combat metastatic melanoma. In early 2009, Dr. Flaherty and his colleague Keiran S Smalley published a mini-review on potential strategies for developing such combination therapies.

During the week of February 22, 2010, the New York Times (NYT) ran a three-part series on a Phase I trial in 2008/2009 of a targeted therapy for metastatic melanoma, a disease that is almost always fatal within a year. The trial was led by Keith T. Flaherty, M.D. (then at the University of Pennsylvania in Philadelphia, and now at the Dana-Farber Cancer Center in Boston). The drug was PLX4032, developed by Plexxikon, which is co-developing the compound with Roche. PLX4032 is a kinase inhibitor, which specifically targets the V600E mutant of the B-Raf oncoprotein. This is the most common somatic mutation found in human melanomas. Researchers believe that B-Raf(V600E) is a “driver mutation” that is particularly critical for the malignant phenotype of human metastatic melanomas that carry the mutation. PLX4032 entered Phase III clinical trials in 2009.

The NYT series, authored by Amy Harmon, focused on the stories of several patients, and on the dogged efforts of Dr. Flaherty to help his patients and to prove the value of targeted therapy. Although the targeted kinase inhibitor imatinib (Novartis’ Gleevec/Glivec) produces complete responses in the majority of treated patients in the chronic phase of CML (chronic myelogenous leukemia) and long-lasting remissions in many of these patients, many researchers believe that this is a special case, and they cite evidence that targeted therapy, especially in solid tumors, almost never produces durable responses. But Dr. Flaherty pressed on with his quest to prove the value of targeted therapy, despite this skepticism.

A key point in the story was when the original formulation of PLX4032, at the highest dose that patients could absorb, produced neither adverse effects nor clinical responses. Because of his belief in targeted therapy, and in this particular drug, Dr. Flaherty convinced Roche to reformulate the drug to enable patients to absorb a higher dose. With the higher doses of the drug made possible by the new formulation, the researchers saw dramatic clinical responses in the great majority of patients whose tumors contained B-Raf(V600E). Responses lasted an average of nearly 9 months, a dramatic breakthrough in treatment of metastatic melanoma.

As the series ended, Dr. Flaherty was working with his colleagues and the pharmaceutical industry to find ways to enable the testing of combination therapies of targeted drugs (including PLX4032) that might result in long-lasting remissions in patients with metastatic melanoma. Meanwhile, Plexxikon and Roche have taken PLX4032 into Phase II clinical trials and now into Phase III.

The NYT series is essentially a human-interest story. I commend it to all researchers, executives, and consultants in the industry whose work does not involve contact with patients, since creating products that can help patients is what our work is all about.

Dr. Flaherty reminds me, and others who have commented on this story, of Brian J. Druker, M.D. at the Oregon Health Sciences University in Portland. It was Dr. Druker’s efforts, centered on helping patients and proving the value of targeted therapy, that was the driving force behind the development of imatinib (Novartis’ Gleevec/Glivec). Without this effort (conducted in collaboration with biochemist Nicholas B. Lydon, then at Novartis), the whole field of kinase inhibitors for targeted therapy of cancer would not have emerged. Dr. Flaherty, as well as several other oncologists, is continuing this worthy tradition.

As pointed out to me by a leading Boston-area academic researcher in a cancer-related area, the NYT series did not give credit to the academic researchers who identified the role of B-Raf in cancer, and especially the role of B-Raf(V600E) in human melanoma. (For that matter, it did not credit the Plexxicon researchers who discovered PLX4032.) She said that the series sounded as if only one person, Dr. Flaherty, was responsible for the development of PLX4032. Moreover, the development of imatinib was made possible by decades of academic research on the target of the drug, Bcr-Abl, a fusion protein formed as the result of a chromosomal translocation. Drs. Druker and Lydon thus were not solely responsible for the development of imatinib either.

The academic researcher has a point. However, some industry commentators take a contrary point of view, downplaying the role of academic researchers in the drug discovery/development process and giving most of the credit to industry.

For years, we have taken the point of view that biology-driven drug discovery and development (arguably the most successful drug discovery/development strategy in the post-genomic era) requires the contributions of both academia and industry, and that more effective collaboration between academia and industry would result in more effective drug discovery and development. (See also my 2005 letter to the editor of BusinessWeek.)

It is basic research, usually in academic laboratories, that has resulted in the very best validated targets. Basic research on a particular target typically takes years or even decades (as in the case of Bcr-Abl). Many of the breakthrough drugs that have emerged in the past 10-15 years (as well as numerous promising pipeline drugs now in clinical testing) were made possible by this research. In contrast, large-scale “target validation” testing in industry more often than not results in targets whose role in normal physiology and in disease is poorly understood. This is an important cause of clinical attrition in drug development.

Nevertheless, it is industry, not academia, which uses this basic research to create drugs. In particular, it is industry that bears the enormous economic risk of drug development, especially of late-stage clinical trials.

Translational researchers, who are involved in taking the results of academic research and/or of discovery research in industry, and translating them into therapies that benefit patients, are—or should be—a key component of the drug discovery-development process. Drs. Druker and Flaherty are two outstanding examples.

However, at least some sectors of academia (and of governmental policy-makers and the media) are suspicious of the type of closer industry-academic collaboration that is needed to produce more effective translation of basic and drug-discovery research into the clinic. An editorial in the 25 February issue of Nature notes that there has been criticism of the recent hiring of William Chin, Lilly’s senior VP for discovery and clinical research, to be the executive dean for research at Harvard Medical School. The critics charge that strong research collaborations between academia and industry will inevitably result in conflicts of interest. The Nature editorial supports institutional policies that require disclosure of links between academic researchers and industry, but deplores the views of influential critics who believe that any collaboration between academic researchers and industry “corrupts” the academic research enterprise.

In addition to Nature, some leading academic researchers say that it is time for industry and the academic medical community to fight back against the critics, rather than appeasing them with ever more restrictive conflict-of-interest policies. These researchers note that the main purpose of medical research is not to publish scientific papers, but to translate this knowledge into therapies that benefit patients. This requires effective collaboration between academia and industry. We agree.

In the December 10 2009 issue of Nature, researchers at Agios Pharmaceuticals (Cambridge, MA) and their academic collaborators published an article implicating mutations in a metabolic enzyme, cytosolic isocitrate dehydrogenase (IDH1) as a causative factor in a major subset of human brain cancers.

The mutated forms of IDH1 are found in around 80% of human grade II-III gliomas and secondary glioblastomas. The mutations occur in arginine 132, which is usually mutated to histidine. (In other less common mutations, arginine 132 is mutated to serine, cysteine, glycine, or leucine.) Typically, only one allele of IDH1 is mutated. These mutations appear to occur early in the process of tumorigenesis, and often appear to be the first mutation that occurs. The mutant forms of IDH1 are also found in a subset of acute myelogenous leukemia (AML).

The wild-type form of IDH1 catalyzes the NADP+-dependent oxidative decarboxylation of isocitrate to α-ketoglutarate. However, the researchers found that the mutant forms of IDH1 no longer catalyzes this reaction, but instead catalyzes the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). This is the result of changes in the active site of the enzyme, as demonstrated by structural studies carried out by the researchers. Tumors that harbor the mutant form of IDH1 have elevated levels of 2HG. The researchers therefore hypothesize that these elevated levels of 2HG are a causative factor in tumorigenesis and/or tumor progression in human gliomas.

This hypothesis is supported by the effects of the familial metabolic disorder 2-hydroxyglutaric aciduria. This disease is caused by a deficiency of 2-hydroxyglutarate dehydrogenase, an enzyme that converts 2HG to α-ketoglutarate. Patients with this metabolic disease have elevated levels of 2HG in bodily fluids and in the brain, and an increased risk of developing brain tumors.

The mechanism by which 2HG might contribute to tumorigenesis is unknown. The authors advance several hypotheses, including increasing reactive oxygen species (ROS) levels, serving as an NMDA (N- methyl-D-aspartate) receptor agonist, and competitive inhibition of enzymes that use glutamate and/or α-ketoglutarate resulting in the induction of hypoxia-inducible factor-1α, a transcription factor that facilitates tumor growth under conditions of hypoxia.

According to the authors, these results suggest that in patients with low-grade gliomas containing mutant forms of IDH1, therapeutic inhibition of 2HG production may slow or halt progression of these tumors to lethal secondary glioblastomas. 2HG levels may also be used as a prognostic test for IDH1 mutations, since patients with these mutations tend to live longer than patients with gliomas that have other mutations.

The company that led this research, Agios Pharmaceuticals, is developing a pipeline of oncology drugs based on targeting metabolic pathways in cancer cells. Interestingly, Agios means “holy” in Greek.

Way back in 1924, Otto Warburg demonstrated a difference between cancer cells and normal adult cells in glucose metabolism. In the presence of oxygen, most normal adult cells metabolize glucose to pyruvate via the process of glycolysis, generating two molecules of ATP (the energy currency of the cell) per glucose molecule. In the mitochondria, they then utilize oxygen to catabolize pyruvate to CO2 and water, in the process generating 36 molecules of ATP per glucose molecule. Cancer cells, however, predominantly carry out aerobic glycolysis, in which they carry out glycolytic conversion of glucose to pyruvate, followed by reduction of pyruvate to lactate. Despite the presence of oxygen, cancer cells generate the bulk of their ATP from glycolysis, not mitochondrial oxidative phosphorylation, in the process consuming large amounts of glucose. The reliance of cancer cells on aerobic glycolysis for their metabolism is known as the “Warburg effect”.

Agios’ platform is based in part on the work of signal-transduction pioneer Lewis Cantley (Beth Israel Deaconess Cancer center/Harvard Medical School, Boston MA). It is Dr. Cantley’s work on the connection between growth factor-mediated signal transduction and aerobic glycolysis that is the basis for Agios’ platform. In particular, Dr. Cantley and his colleagues found that pyruvate kinase M2 (PKM2) is a link between signal transduction and aerobic glycolysis. PKM2 binds to tyrosine-phosphorylated signaling proteins, which results in the diversion of glycolytic metabolites from energy production via mitochondria oxidative phosphorylation to anabolic processes required for rapid proliferation of cancer cells.

Agios closed a $33 million Series A financing in July 2008, co-led by Third Rock Ventures, Flagship Ventures and ARCH Venture Partners. In June 2009, Fierce Biotech named Agios to the 2009 FierceBiotech “Fierce 15” list. On December 21, 2009, Agios received funding from the nonprofit organization Accelerate Brain Cancer Cure (ABC2), to supplement Agios’s research on the development of IDH1-based therapeutics and diagnostics. Agios expects to have a lead compound in the clinic some time in 2010.

The Agios website calls cancer metabolism “one of the most exciting new areas of cancer research”. But the study of cancer metabolism, and especially the Warburg effect, is not new—the Warburg effect is a classic observation going back 85 years. Moreover, biotechnologists working in such areas as production of recombinant proteins in CHO cells have been familiar with aerobic glycolysis, which is carried out by most mammalian cell lines in culture, for decades. Nevertheless, cancer metabolism has been well out of the mainstream of cancer drug discovery. It was Dr. Cantley’s work, which links the classic Warburg effect to the mainstream area of signal transduction and protein kinases, which has made Agios’ platform possible.

Similarly, it was Julian Adams’ work on the biology of the proteasome in the 1990s, through a series of biotechnology company mergers that eventually led him to Millennium Pharmaceuticals (now Millennium: The Takeda Oncology Company), which resulted in Millennium’s proteasome inhibitor Velcade (bortezomib). Velcade, the only proteasome inhibitor on the market, is now approved by the FDA for the treatment of multiple myeloma and mantle cell lymphoma. Prior to Dr. Adams’ work, proteasome biology and protein degradation were out of the mainstream of cancer drug discovery. Now Joseph Bolen, the chief scientific officer of Millennium, sees “protein homeostasis” as one of the most exciting areas of cancer research.

Finally, although the development of protein kinase inhibitors to target signaling pathways in cancer is now well within the mainstream of oncology drug discovery, prior to the discovery and development of imatinib (Novartis’ Gleevec/Glivec) (approved by the FDA in 2001), specific targeting of protein kinases was though to be unlikely, since all of these enzymes have a high degree of similarly in their ATP binding sites. Thus the field of protein kinase inhibitors did not enter the mainstream until the late 1990s-early 2000s.

The take-home lesson is that drug developers may find fertile areas for innovation in seemingly obscure or out-of-the mainstream areas of biology (or of chemistry, as we have discussed in previous blog posts). Some of these areas may be technologically premature, and not quite ready for exploitation by drug developers. However, as demonstrated by our blog post on monoclonal antibodies, even some technologically premature areas may yield to innovators who are willing and able to develop enabling technologies to move these areas up the development curve.