The time for the July 2011 World Drug Targets Summit in Cambridge MA is looming closer and closer! Registration for the conference is still open, however.

I will lead a workshop entitled “Developing Improved Animal Models in Oncology and CNS Diseases to Increase Drug Discovery and Development Capabilities” at the Summit on July 19.  A workshop on addressing kinase signaling in drug discovery and development will take place later that day. The main conference follows on July 20-21. I am planning to attend the entire conference.

Our workshop will be a discussion of four case studies involving development of novel animal models in oncology and CNS diseases, aimed at more closely modeling human disease than current models. Drug discovery and development in these therapeutic areas has been severely hampered by animal models that are  poorly predictive of efficacy. This is a major cause of clinical attrition in these areas.

There will be one case study on a zebrafish cancer model, two on mouse cancer models, and one on a mouse CNS disease model. The case studies will include applications of these animal models to understanding disease biology, developing new therapeutic strategies, overcoming resistance to breakthrough targeted cancer therapeutics, and identifying drug candidates and advancing them into the clinic.

The main conference will focus on developing improved target discovery and validation strategies that are capable of meeting the challenges of drug discovery and development in the early 21st century–minimizing drug attrition in the clinic, and delivering commercially differentiated products that address unmet medical needs to the market. Speakers will include target discovery and validation leaders from leading pharmaceutical companies, biotechnology companies, and academic institutions.

On June 1, 2011, Cambridge Healthtech Institute’s (CHI’s) Insight Pharma Reports announced the publication of our new book-length report, Multitargeted Therapies: Promiscuous Drugs and Combination Therapies.

In the past 20 years or so, pharmaceutical and biotechnology industry R&D has been increasingly aimed at developing drugs to treat complex diseases such as cancer, cardiovascular disease, type 2 diabetes, and Alzheimer’s disease. However, the one drug-one target-one disease paradigm that has become dominant in the post-genomic era has proven to be inadequate to address complex diseases, which have multiple “causes”, and each of which may be more than one disease. This has been a major cause of clinical failure and the low productivity of the pharmaceutical industry.

Moreover, researchers have found that most of the successful, FDA-approved small-molecule drugs that were developed prior to the year 2000 are promiscuous, i.e., they are single drugs that address multiple targets. In addition, the great majority of kinase inhibitors, one of the most successful drug classes of the early 21st century, are also promiscuous.

The study of small-molecule drug promiscuity has spawned the emerging field of network pharmacology, which can be applied both to study drug promiscuity and to rationally design small-molecule multitargeted drugs. (Researchers can discover or design multitargeted kinase inhibitors without the use of network pharmacology, however.)

Meanwhile, the development of targeted drugs such as kinase inhibitors and monoclonal antibodies has resulted in the need to develop multitargeted combination therapies. This has been especially true in cancer, where disease causation may involve multiple signaling pathways. In particular, the development of resistance to targeted antitumor drugs has spawned the need to develop second-generation treatments, many of which are multitargeted combination therapies.

Our report covers both discovery and design of small-molecule promiscuous/multitargeted drugs, and of multitargeted combination therapies.

The design of multitargeted combination therapies is one of the hottest areas of cancer R&D today, especially with respect to developing means to overcome resistance to targeted therapies. This area was the focus of many key presentations at the 2011 American Society of Clinical Oncology (ASCO) Annual Meeting, which was held in Chicago on June 3-7. For example, treatment with vemurafenib (PLX4032) of metastatic melanoma patients whose tumors carry the B-Raf(V600E) mutation has produced spectacular overall response rates and increased survival. However, in nearly all cases, the tumors relapse. The latest results with vemurafenib were discussed at ASCO 2011, as well as strategies to overcome resistance to therapy. Our new report also discusses strategies for overcoming vemurafenib resistance, all of which involve design of multitargeted combination therapies.

Another topic discussed at ASCO 2011 was antitumor strategies based on synthetic lethality. We discussed this strategy in an earlier article on this blog, especially with respect to poly(ADP) ribose polymerase (PARP) inhibitors such as KuDOS/AstraZenaca’s olaparib. At a session at the ASCO meeting entitled “PARP Inhibitors, DNA Repair, and Beyond: Theory Meets Reality in the Clinic”, speakers reviewed current progress in developing PARP inhibitors, of which six are now in clinical development.

This session also included a presentation by Michael B. Kastan, MD, PhD (St. Jude Children’s Research Hospital, Memphis TN) on other ways of using the synthetic lethally strategy, for example by targeting kinases involved in DNA repair pathways such as ATM (Ataxia-Telangiectasia Mutated) or Chk1 checkpoint kinase, or even utilizing features of the tumor microenviroment such as hypoxia. Such strategies might be used to design multitargeted combination therapies that specifically target cancer cells with defects in DNA repair and/or in hypoxic solid tumors, and/or to sensitize cancer cells to radiation.

Our new report includes a chapter on using the synthetic lethality strategy to design combination therapies of a cytotoxic drug with a chemosensitizing agent, and to develop therapies for p53-negative cancers. (The key tumor suppressor p53 is deleted, mutated, or inactivated in the majority of human cancers).

Although design of multitargeted combination therapies, as well as discovery and design of kinase inhibitors, are of key importance for current oncology R&D and are also being applied to other diseases, design of single small-molecule multitargeted drugs via network pharmacology is an early-stage, and perhaps a premature, technology. Nevertheless, given the current pharmaceutical company R&D business model that emphasizes outsourcing early-stage R&D, academic research groups and biotechnology companies that are active in this area may be able to forge partnerships with pharmaceutical companies.

For more information on Multitargeted Therapies: Promiscuous Drugs and Combination Therapies, or to order it, see the Insight Pharma Reports website.

I will lead a workshop entitled “Developing Improved Animal Models in Oncology and CNS Diseases to Increase Drug Discovery and Development Capabilities” at the World Drug Targets Summit in Cambridge MA in July 2011.

Workshops will be held on July 19, and the main conference on July 20-21. I am planning to attend the entire conference.

Our workshop will be a discussion of 2-3 case studies involving development of novel animal models in oncology and CNS diseases, aimed at more closely modeling human disease than current models. Drug discovery and development in these therapeutic areas has been severely hampered by animal models that are  poorly predictive of efficacy. This is a major cause of clinical attrition in these areas.

We shall discuss the implications of these case studies for developing novel therapeutic strategies, target identification and validation, drug discovery, preclinical studies, and reducing clinical attrition. We shall also discuss hurdles to industry adoption of novel animal models developed in academic laboratories.

The main conference will focus on ways of building successful target strategies to minimize drug attrition in the clinic, and specifically how to identify and validate targets that can lead to commercially differentiated products. Speakers will include target discovery and validation leaders from such companies as Pfizer, Merck, NeurAxon, Gilead Sciences, Boehringer Ingelheim, Merrimack Pharmaceuticals, Bayer Schering Pharma AG, FORMA Therapeutics, Roche, Novartis, Tempero Pharmaceuticals, UCB Pharma, Infinity Pharmaceuticals, and from such academic institutions as Harvard Medical School.

The conference agenda and brochure, as well as online registration, are available on the conference website.

Galega officinalis (Goat’s Rue) From JoJan http://bit.ly/l5Ybco

Metformin (Bristol-Myers Squibb’s Glucophage, generics), an oral biguanide antidiabetic drug, is the most widely prescribed agent for treatment of type 2 diabetes. The drug mainly works by lowering glucose production by the liver, and thus lowering fasting blood glucose.

Although metformin–approved in the United States in 1994, and in Europe prior to that–has been used for many years, its mechanism of action is not well understood. In 2005, signal-transduction pioneer Lewis Cantley (Beth Israel Deaconess Cancer Center/Harvard Medical School, Boston MA), and his colleagues–including Reuben J. Shaw (now at the Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA)–published a report showing that metformin targets the adenosine monophosphate (AMP)-activated kinase (AMPK) pathway in the liver. We discussed this report and its implications in our 2007 Cambridge Healthtech Institute Insight Pharma Report, Diabetes and Its Complications.

AMPK is found in all eukaryotic organisms, and serves as a sensor of intracellular energy status. In mammals, it also is involved in maintaining whole-body energy balance, and helps regulate food intake and body weight. We  have discussed the potential role of AMPK in regulation of lifespan, and as a target in anti-aging medicine and in metabolic disease, in earlier articles on this blog. (See here and here.)

AMPK is activated by increases in the ratio of AMP to ATP, caused by energy stress. Under conditions of energy stress, AMP levels go up, and AMP binds to a specific site on the AMPK γ subunit. This induces a conformational change that exposes the activation loop of the α subunit. This allows an upstream serine/threonine kinase to phosphorylate this activation loop. In several mammalian cell types, including liver and skeletal muscle, that kinase is LKB1. Drs. Cantley and Shaw in 2005 showed that metformin targets the LKB1-AMPK pathway in the liver, and that metformin requires LKB1 to lower glucose production by the liver. However, neither LKB1 nor AMPK is the direct target of metformin, and as of 2005, that direct target was unknown.

A new genetic study that suggests that ATM kinase may affect the ability of patients to respond to metformin

Now–as of February 2011–comes a Nature Genetics paper that indicates that the serine/threonine kinase ATM (ataxia telangiectasia mutated) acts upstream of AMPK to mediate the therapeutic effects of metformin. ATM is a DNA repair protein that is recruited and activated by double-strand breaks in DNA. It initiates activation of the DNA damage checkpoint, leading to cell cycle arrest, followed by DNA repair or apoptosis. Thus the role of ATM in the AMPK pathway and in the therapeutic effects of metformin is surprising indeed.

In the study reported in the Nature Genetics paper, researchers of The GoDARTS and UKPDS Diabetes Pharmacogenetics Study Group and The Wellcome Trust Case Control Consortium 2 performed a genome-wide association study (GWAS) for glycemic response to metformin in type 2 diabetes patients in the U.K. In a population of nearly 4,000 patients, they identified a single-nucleotide polymorphism (SNP) designated rs11212617, which was associated with treatment success. This SNP occurs in a genetic locus that also contains the gene that encodes ATM. In a rat hepatoma cell line, inhibition of ATM by the specific inhibitor KU-55933 (KuDOS Pharmaceuticals, Cambridge, U.K., which was acquired by AstraZeneca in 2005) attenuated metformin-mediated phosphorylation and activation of AMPK.

The analysis by Morris Birnbaum and Reuben Shaw in the 17 February 2011 issue of Nature

The 17 February 2011 issue of Nature contained a Forum entitled “Genomics: Drugs, diabetes and cancer.” This consisted of two analyses of the implications of the Nature Genetics paper for metformin’s mechanism of action, and for understanding diabetes and the connections of the metformin-activated ATM/AMPK pathway with cancer. The first analysis was by Morris J. Birnbaum, M.D., Ph.D. (University of Pennsylvania Medical School, Philadelphia, PA), who does research on the role of AMPK and insulin in energy metabolism and in diabetes. The second analysis is by Dr. Reuben Shaw, mentioned earlier. Dr. Shaw’s research centers around LKB1 [also known as serine/threonine kinase 11 (STK11)]. LKB1, a serine/threonine kinase, is not only a regulator of hepatic glucose production via AMPK, but is also a tumor suppressor. Germline mutations in LKB1 are associated with the familial cancer Peutz-Jegher syndrome, and somatic mutations in LKB1 are present in various other cancers. In particular, the Lkb1 gene is one of the most frequently muted genes in human lung adenocarcinomas.

Dr. Birnbaum’s analysis

Dr. Birnbaum notes that the finding of a role for ATM in metformin responsiveness may be an important clue to the mechanism of action of this drug. However, it may also be a false lead, with ATM having only an indirect effect on metformin’s action. He cites recent evidence that metformin acts independently from LKB1 and AMPK and of transcriptional regulation in general. In these studies, genetic ablation of LKB1 and AMPK was used to show that these mediators are dispensable for metformin’s glucose-lowering activity. Instead, metformin appears to work by inhibiting mitochondrial production of ATP in the liver, thus reducing the level of liver glucose production via gluconeogenesis (which uses ATP). This is in apparent contradiction to the 2005 results of Dr Shaw and his colleagues. Nevertheless, metformin’s inhibition of mitochondrial ATP production increases the ratio of AMP to ATP, and thus activates AMPK. There are also other pathways by which inhibition of mitochondrial ATP production may inhibit gluconeogenesis. Thus the mechanisms by which metformin causes a decrease in glucose production by the liver appear to be very complex, and are not well understood.

Dr. Birnbaum therefore speculates that ATM may affect blood glucose levels via pathways that are parallel to, but not the same as, those modulated by metformin. However, the effects of these other pathways may be synergistic with those modulated by metformin when patients are treated with the drug. Dr. Birnbaum notes that 40 years ago, it was found that patients with ataxia telangiectasia often display a type 2-diabetes-like condition, including insulin resistance. Ataxia telangiectasia is a familial disease caused by germline mutations in ATM. This suggests that  ATM may act to counteract hyperglycemia and insulin resistance.

Dr. Birnbaum concluded that biochemical and cell biology studies should be conducted to determine the nature of the interaction of ATM and the antidiabetic effects of metformin. Key to these endeavors is to determine whether there are any biomolecules other than AMPK that both are influenced by ATM and control metabolism.

Dr. Shaw’s analysis

Dr. Shaw first discusses several animal studies that help elucidate the role in glucose regulation of the biomolecules involved in the putative ATM-LKB1-AMPK pathway. He notes notes that deletion of the Lkb1 gene in mouse liver results in loss of AMPK activity in that organ, and to the development of hyperglycemia and hepatic steatosis–two conditions that are seen in type 2 diabetes. Dr. Shaw also cites the 40-year-old finding about the connection between  ataxia telangiectasia and insulin resistance and diabetes. But as he also mentions the more recent (2006) finding that mice with defective ATM activity show increased insulin resistance and abnormal glucose regulation.

Dr. Shaw then speculates as to how ATM might work to modulate patients’ antidiabetic responses to metformin. He notes that ATM is known to phosphorylate LKB1, which is the key activator of AMPK in the liver. Alternatively, ATM might also regulate AMPK independently of LKB1, and might affect responsiveness of patients to metformin by regulating other relevant targets, independently of AMPK. In this context, ATM is known to phosphorylate other, LKB1 and AMPK-independent components of the insulin signaling pathway.

In the light of these considerations, Dr. Shaw says that it is important to determine whether the rs11212617 genetic variant results in modulation of ATM activity toward AMPK activation or toward other targets relevant to glucose regulation, or indeed whether this SNP affects ATM activity at all.

Dr. Shaw then focuses on the potential relevance of metformin to cancer therapy. Researchers have found, in retrospective studies, that diabetes patients who take metformin have a lower risk of developing cancer than those treated with other antidiabetic medications. Animal studies confirm the anticancer effects of metformin, but–as discussed in a 2010 review by Dr. Michael Pollak (McGill University, Montreal, Quebec, Canada)–they indicate that the anticancer effects of this drug are mechanistically complex. Dr. Shaw asks whether metformin is a general activator of ATM (and/or its targets) in the DNA damage-response pathway, or whether its specific effects on LKB1 and/or AMPK might be responsible for the apparent beneficial effects of metformin on cancer risk.

Dr. Shaw concludes with the statement that future studies of the relationship between metformin action, ATM, LKB1, and AMPK should shed light on the relationship between metformin’s antidiabetic effects and its apparent anticancer effects.

Our conclusions

The finding, based on a genome-wide association study, which suggests that ATM, a kinase best known for its involvement in DNA repair pathways, may also be involved in diabetics’ response to metformin is surprising and intriguing. It may eventually be important in unraveling metformin’s mechanism of action in inhibition of liver gluconeogenesis, and in other antidiabetic activities. This finding indicates a connection between pathways by which metformin exerts its antidiabetic activities, and pathways that are involved in cancer.

Nevertheless, the elucidation of metformin’s mechanism(s) of action in diabetes remains a work in progress. This situation is an example of how science works in the real world (as opposed to textbooks or much of science journalism)–generating more questions than answers.

A drug like metformin, with its complex and still poorly understood mechanism of action, could not have been discovered by modern, post-genomics drug discovery strategies. Metformin was discovered via research on natural products derived from the plant Galega officinalis (known as the French lilac, goat’s rue, and by various other names), which had been known by herbalists for centuries. It is fortunate that researchers were able to study the effects of extracts of this plant, and ultimately to develop metformin, well in advance of the modern era of drug discovery. Diabetics and their physicians now have access to metformin as an inexpensive generic drug.

The continued study of the antidiabetic mechanism(s) of action of metformin may yield additional insights into control of gluconeogenesis and other metabolic pathways. Some of the findings of these studies might be relevant to drug discovery and development, for example the development and use of AMPK activators in metabolic disease and in anti-aging medicine.

Continued study of the mechanism(s) of action of metformin may also be relevant to developing new therapies for cancer. As suggested by Dr. Pollak, although metformin is off-patent and is thus not an attractive agent for development as an oncology drug by pharmaceutical or biotechnology companies, other biguanides or related compounds might be better anticancer compounds, and would be patentable. In addition to identifying such compounds, it will be important to determine and define which groups of cancer patients could best benefit from them (perhaps via biomarkers). It will then be important to conduct personalized medicine hypothesis-testing clinical trials (as discussed in an earlier blog post) designed to obtain proof-of-concept that such compounds can indeed benefit specific groups of patients.

___________________________________

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.

Red blood cell, platelet, and lymphocyte

Since the publication of our March 30, 2011 article on melanoma on this blog, interest in melanoma has remained high. This is to be expected, with the March 2011 approval of ipilimumab (Medarex/Bristol-Myers Squibb’s Yervoy), and the expected approval of Daichi Sankyo/Plexxikon/Roche’s PLX4032/RG7204 in the near future.

The April 2011 issue of the Faculty of 1000’s The Scientist included two articles that focused on melanoma. The first article, entitled “Taking Aim at Melanoma”, was written by leading clinician and scientist Keith T. Flaherty, M.D., whose work (especially with respect to development of PLX4032) has been discussed in  several articles on this blog. The second article, which we shall discuss further below, is entitled “Imagining a Cure”.

Then there was the American Association for Cancer Research (AACR) meeting (April 2-6, 2011, Orlando FL). This included numerous presentations on melanoma, including strategies for overcoming resistance to PLX4032 via development of combination therapies. There were parallel discussions on similar strategies in other cancers.

Haberman Associates will have a major new publication out shortly. This will (among other things) include discussions of combination therapies designed to overcome resistance to targeted therapies in several cancers, including melanoma.

The article entitled “Imagining a Cure” in The Scientist was written by National Cancer Institute (NCI) principal investigator Nicholas P. Restifo, M.D., and writer Megan Bachinski.

This article begins with what is the real desire of every cancer patient–a durable complete response, which is tantamount to a cure. In the case of patients with early-stage, localized melanoma, the disease is completely curable via surgery. However, metastatic melanoma is almost always fatal. Pre-March 2011 treatments, dacarbazine and interleukin-2 (IL-2), have reported complete response rates of 2.7 percent and 6.3 percent respectively. Even the newer treatments, ipilimumab and PLX4032, although they give improved survival over earlier treatments, only have reported rates of durable complete responses of 0.6 percent and 2.0 percent, respectively.

The authors then go on to discuss the only type of therapy that has resulted in high percentages of durable compete responses in metastatic melanoma patients–adoptive cell transfer (ACT), also known as adoptive immunotherapy. Dr. Restifo works in this area, as well as in other aspects of tumor immunology. Adoptive immunotherapy was pioneered by Steven A. Rosenberg, M.D. Ph.D., the Chief of Surgery and Head of the Tumor Immunology Section at the NCI, since the 1980s. Dr. Rosenberg remains a leader in the field, and Dr. Restifo works with him.

In ACT, a physician/researcher extracts a patient’s antigen-specific immune cells, which are usually found in tumor tissue. [Such cells are known as “tumor infiltrating lymphocytes” (TILs).] He or she then expands the numbers of the antitumor T lymphocytes in cell culture, using the T-cell growth factor, IL-2. The physician/researcher then infuses the cells, plus IL-2, intravenously into the patient. The infused T cells traffic to tumors and can mediate their destruction. Prior to TIL infusion, the patient may have his or her immune system temporarily ablated via “preparative lymphodepletion” with chemotherapy and sometimes also total-body irradiation. The preparative lymphodepletion treatment is associated with enhanced persistence of the transferred TILs.

In a recent clinical study of ACT, the treatment resulted in the disappearance of all tumors in 20/93 patients (21.5%) with advanced metastatic melanoma. For 19 of these 20 patients (95%), the complete responses have been durable and long-lasting, in some cases lasting for over 7 years. (See also the Faculty of 1000 evaluation.)  Research on the mechanistic basis of adoptive immunotherapy, as well as on means to improve ACT technologies, is ongoing, so there is the potential to improve the durable complete response rate further.

Adoptive immunotherapy is not the only cancer immunotherapy that is in clinical studies or on the market. The newly-approved ipilimumab is a nonspecific T-cell modulator. Then there are the therapeutic cancer vaccines, including sipuleucel-T (Dendreon’s Provenge), which was approved for treatment of prostate cancer in 2010, as well as other cancer vaccines in clinical trials. Sipuleucel-T, which costs about $93,000, provides only a modest survival benefit (in one Phase 3 trial, 25.8 months compared to 21.7 months for placebo-treated patients) and is not associated with tumor regression. Overall, cancer vaccine clinical trials have resulted in an overall response rate of less than 4 percent. There have been no complete responses.

The authors of the article ask the following questions: If adoptive immunotherapy for metastatic melanoma has such a high durable complete response rate, why is it only available in a small number of cancer canters worldwide? Why is there little commercial interest in developing ACT? What can be done to facilitate the more widespread adoption of adoptive immunotherapies?

The authors give the following explanations: Adoptive immunotherapies are still considered experimental, are not FDA-approved, and are not paid for by third party payers. Thus only a handful of locations can bear the financial burden of administering adoptive immunotherapy. However, if a cancer center has a cell production facility with the required staff, the cost of producing a single dose of T-cells for adoptive transfer is approximately $20,000, much lower than a full course of Provenge or ipilimumab (approximately $120,000) treatment. ACT treatment also entails factoring in the cost of hospitalization. Most patients only require a single dose, however.

Adoptive immunotherapy is also comparable or less expensive than the cost of other, non-immunotherapy antitumor biologics, such as bevacizumab (Avastin) or cetuximab (Erbitux)—where the cost of the drug alone can exceed $80,000, and no patients are cured.

Moreover, according to the article, it would be difficult for a private company to pursue clinical trials for FDA approval and commercialization of ACT. To conduct such trials, a company would need to build a specialized cell processing and treatment facility, with a highly trained and competent staff. Adoptive immunotherapies also appear to lack a clearly defined claim to intellectual property (IP), since the patient’s own cells are not a “drug” to be patented. Nevertheless, Provenge also uses the patient’s own cells (in this case, antigen-presenting dendritic cells), and must be prepared specifically for each patient. In the case of Provenge, the cells are combined with a proprietary antigen/growth factor fusion protein (PA2024), however.

In the case of adoptive immunotherapies, various technologies for TIL isolation, selection, and expansion might be patentable, as might the use of genetically-engineered antitumor T cells.

The public sector might, according to the article’ authors, provide an alternative sponsor for adoptive immunotherapy. A network of cancer centers, institutes, and hospitals might form a consortium to refine ACT technology, and sponsor clinical trials aimed at FDA approval. Such FDA approval might provide substantial financial benefits for institutions in the consortium.

Moreover, research is underway to expand the types of cancers to be treated via adoptive immunotherapy. This research involves adoptive immunotherapy for synovial-cell sarcomas, B-cell lymphomas, and renal cancer. The expansion of adoptive immunotherapy beyond melanoma might, according to the authors, bring in new groups of stakeholders with an interest in making this type of treatment more widely available. Moreover, it might also encourage corporate and/or nonprofit organizations to envision the possibility of treating more common cancers, with the potential for larger financial rewards.

Given the superior results in terms of durable complete responses and comparable costs to other types of metastatic melanoma treatments, and the potential to treat other cancers, adoptive immunotherapy should not be ignored. However, it faces considerable hurdles to its widespread adoption.

________________________________

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.