Repurposing and Combining Drugs – An Effective Cancer Treatment Strategy

Dr Robert Nagourney is the founder and medical director of Nagourney Cancer Institute, and clinical professor at the University of California, Irvine School of Medicine. Nagourney is having success investigating whether a unique combination of existing and approved cancer drugs might be more effective compared to “off-the-shelf” treatments. Technology Networks recently had the pleasure of speaking with Nagourney to learn more about his work focused on repurposing drugs. He discusses the challenges and benefits of exploring new uses for drugs that are outside the scope of their original indication. He also shares a case whereby a cancer patient was recently treated with a tailored drug combination and explains how it was possible to design an effective personalized treatment strategy.

Laura Lansdowne (LL): Can you touch on the importance of physiological relevance when testing therapeutics in in vitro systems, has there been any key advances in cell culture technologies that have been particularly effective at improving this? 

Robert Nagourney (RN): The wide use of genomic profiling by next-generation sequencing (NGS) has provided targetable mutations in a number of cancers including chronic myeloid leukemia (CML), several forms of lung cancer, kidney cancers and melanoma. However, the majority of human tumors do not reveal “actionable” mutations. Today these tumors are treated with cytotoxic chemotherapy or experimental drugs with no attempt to select among options and offer combinations that are patient specific. To address patients’ needs we developed the “Ex Vivo Analysis of Programmed Cell Death” or “EVA/PCD” platform.

Two fundamental advances have led to the successful application of our EVA/PCD technology for the prediction of patient response over older technologies.

1.  The measurement of drug induced cell death as opposed to platforms that measured drug-induced growth inhibition. These failed methodologies included the clonogenic (stem cell) assay, the DNA synthesis (H3*Thymidine incorporation) assays and other growth-based techniques. Cancer doesn’t grow too much – it dies too little. Measuring growth inhibition is irrelevant.
   
   
2. The second advance was the recognition of cancer as a dysregulated system and not an abnormal cell. Cancers communicate and reverberate with their microenvironment. Indeed, the microenvironment creates the state of malignancy and certainly contributes to the survival and drug resistance of tumor populations. To address cancer’s true biology, one must study three-dimensional cell culture models (organoids) as we have done successfully for many years.

 
LL: Could you tell us more about your work repurposing drugs?  

RN: Drugs do not know what diseases they were invented for. This not only applies to drugs for cancer but to other drugs with biological effect that can influence cancer cell behavior.

LL: In your blog you share the story of a Stage 4 gastroesophageal cancer patient that was recently treated with a tailored drug combination. Could you elaborate on the “genetic clue” that helped design an effective combination therapy?  

RN: The patient was found sensitive to a drug that targets EGFR a cell signaling pathway. However, he did not have a mutation in EGFR. As such his doctors did not anticipate a likelihood of benefit from drugs that target EGFR and did not offer him these agents. In our EVA/PCD we found activity for these drugs. When we reviewed his gene profile it showed an EGFR amplification (not a mutation). Since EGFR amplification is not considered a target, no drug was offered but with the discriminating (functional) capability of the EVA/PCD assay, he indeed was that rare person with an EGFR amplification who would actually likely respond and when we gave it to him he did… Completely!

LL: When repurposing a drug, how careful do we need to be when considering existing safety and efficacy data? E.g. data that were obtained in previous studies, for different indications, in a different study population (age/sex/ethnicity, etc.).

RN: Any novel combination runs some risk, but many repurposed drugs are already in wide use, and very often are used in combination with many other drugs. I am not a proponent of “random combinations” (however many commercial firms do offer them) but instead like to examine the patient's likelihood of benefit when we do suggest a drug or combination.

LL: What measures/approaches should be taken when considering off-label use of a drug? 

RN: Usually these drugs are well known for their modes of action and toxicity. The literature provides ample information on drug–drug interactions and usually can be consulted if an unusual combination is being considered. 

LL: There is currently no regulatory requirement to know the molecular target of a drug, as long the drug is shown to be safe and efficacious. How much of a drawback does this “gap in knowledge” present, in terms of repurposing existing drugs for other indications?  

RN: Actually, many new drugs come with companion diagnostics. That is, you can only get a TRK inhibitor if you are shown to carry and NTRK fusion. Where functional platforms can be immensely helpful is the vast amount of genomic regulation and cellular gene activity that cannot be identified at a genetic level. One perfect example in the oncogene MYC. This super-regulator that functions epigenetically is abnormally active in up to 70% of cancers, it regulates over 3600 individual human genes (15% of the human genome) and is almost never mutated – ever.  Thus, it is only by probing its activities at a functional level that you know to target it therapeutically. Gene profiles are useless.

Robert Nagourney was speaking with Laura Elizabeth Lansdowne, Senior Science Writer for Technology Networks.

Interviewee Biography

Dr Nagourney is a native of Connecticut and a graduate of McGill University School of Medicine and became disenchanted with the trial and error approach that he witnessed during fellowships at Georgetown and The Scripps Institute. Nagourney is currently a practicing oncologist and triple board certified in Internal Medicine, Medical Oncology and Hematology. Among his many accomplishments, as co-investigator on national cooperative trials. He is recognized for the introduction of Cisplatin/Gemcitabine doublets in the treatment of advanced ovarian and breast cancers.

With more than 20 years of experience in human tumor primary culture analyses, Dr Nagourney has authored more than 100 manuscripts, book chapters and abstracts including publications in the Journal of Clinical Oncology, Gynecologic Oncology, the Journal of the National Cancer Institute and British Journal of Cancer.