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The Success of Personalized Anti-Cancer Therapies

Posted on January 4th, 2017 by in Pharma R&D


Every day, thousands of cancer patients face difficult choices about their treatment options. For those affected by advanced, stage 4 cancer, the decisions can be particularly painful. With very little time left for action, perhaps weeks, and oftentimes with multiple experimental treatment options available, none with guaranteed success, they have just one chance at choosing the best one possible.

For some clinical oncologists, including my collaborator Dr. Francisco Castillos of Personalized Hematology-Oncology of Wake Forest (NC), the solution lies in applying a personalized medicine. In a recent paper published in the International Journal of Cancer and Clinical Research[1], we describe a new methodology used to help three patients who came to Wake Forest as a last resort, after having exhausted all standard-of-care treatment options at major hospitals. By developing a personalized anti-cancer therapy based on a signaling pathway analysis of the tumors, all the patients outlived the overall survival estimates based on standard-of-care treatment.

Our approach is two-pronged: (1) determining the molecular mechanism driving tumor proliferation in a given patient, and (2) matching the patient with the best FDA-approved drug available that targets the molecular mechanism uncovered. Using cutting-edge technology that combines Next Generation Sequencing and gene expression profiling with huge knowledge databases, the analysis and calculations can be done in as little as one day. The methodology offers instant information on the current makeup of the cancer affecting the patient and identifies the drug on the market with highest chances to be effective against the particular proliferation mechanism driving that cancer. With this approach, which is currently applicable to any type of solid tumor with more than 50 percent of viable tumor cells, stage 4 cancer patients who face their last chance at treatment can take action immediately, directly targeting the mechanism that drives proliferation of their tumor.

The Personalized Hematology-Oncology clinic relies on a CLIA-certified clinical laboratory to generate expression data from patient biopsies using the microarray gene chips, and then uses Elsevier’s Pathway Studio in-house to interpret the results, finding cancer-related signaling pathways driving the changes in gene expression observed in the tumor relative to normal tissue.[2] The identified pathways, involved in their particular cancers, point clinicians either to existing FDA-approved drugs that can be effective for the molecular mechanism of action observed in the tumor or to the appropriate clinical trials.

Our vision for the immediate future of cancer treatment is not limited to helping stage 4 cancer patients. In 21st century medicine, a more effective management of early-stage cancer will involve a change of paradigm as well: from classical diagnosis and categorization of cancers based on pathological and clinical hallmarks (which may bear limited relevance to the actual molecular drivers of tumor growth for each individual patient at any given point in time), to molecular profiling of the tumors in a patient, combined with selection of individualized therapies based on the molecular profile of the tumors. This new paradigm can represent a better alternative to the “one-treatment-fits-all” model used under the 20th century standard of care approach such as chemo-, radiation, or hormonal therapies.

Currently, medical treatment is delivered around the so-called standard of care, which refers to the diagnostic or treatment process that health care providers should follow for a certain category of patient, disease, or clinical situation. For example, a standard treatment plan for some classes of cancer may include surgery to remove a tumor or chemotherapy with cytotoxic agents, regardless of the genetic expression profile that the tumor may exhibit in a patient. Although the term “standard of care” has a clear definition in legal terms and is an essential component of an action in medical malpractice, there is actually no medical definition for it.[3] Communities or hospitals establish certain standards of care by consensus, but these standards may not be the only ones — or even the best ones. And when it comes to cancer, which is highly complex, as well as individualized and specific, it may be simply not possible to develop a standard of care based on averages that is effective for all patients. Indeed, standard cancer treatments can fail in half of the patients or more.

In contrast, an approach employing an individualized gene expression profile allows oncologists to evaluate the “blueprint” of a patient’s tumor and to determine which drugs have the capacity to prevent tumor proliferation or which treatments may or may not have a chance to be effective for that particular tumor. Molecular data can provide critical information to make decisions about treatment course, participation in clinical trials, or whether to pursue further therapy, which will be directly relevant to each individual patient. In addition, selection of patients for clinical trials based on the molecular profile of the tumor can significantly improve chances for the trial success.

This new methodology for the development of personalized therapies can revolutionize the treatment of other complex diseases, not just cancer. Indeed, every year millions of patients suffering this type of diseases — such as multiple sclerosis, high cholesterol, asthma, schizophrenia, or depression — are prescribed medications that will prove ineffective for them. According to a 2015 comment in Nature[4], the ten top-selling drugs in the U.S. at best help 1 in 4 of the patients using them (Humira for arthritis, Enbrel for psoriasis, Remicade for Crohn’s disease), or in the worst case just 1 in 24 (Nexium for heartburn). Part of the reason is the genetic complexity underlying these diseases, with variability from person to person. Another reason has to do with the individual factors that determine a person’s response to treatments.

The methodology that we are now applying to stage 4 cancers can be in principle applied to any disease for which a tissue biopsy is available and a genomics profile can be evaluated. This would allow the elucidation of the disease mechanism at work in an individual patient suffering from a complex disorder, providing important information to develop an effective treatment plan.

We envision the use of the pathway analysis methodology not only to uncover the molecular mechanism at work in the disease suffered by an individual patient but also to tap onto the existing repository of therapeutic drugs already on the market. In the last 25 years, hundreds of FDA-approved drugs have become available, with very well-known mechanisms of action. With this approach, it would be possible to identify which of them may be the best choice for a given patient, based on what is driving his or her disease at a molecular level.





Click here to access our free whitepaper entitled “The Impact of Modern Disease Biology Solutions on Pharmaceutical Development.”


All opinions shared in this post are the author’s own.

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