Synergistic Drug Combinations Provide Better Outcomes for Cancer Patients

Among the most sought after attributes of chemotherapy drug combinations is drug synergy. Synergy, defined as supra-additivity wherein the whole is greater than the sum of the parts, reflects an elegant interaction between drugs predicated on their modes of action. While some synergistic interactions can be predicted based upon the pharmacology of the agents, others are more obscure.

We have extensively examined the synergy between classes of drugs based on known modes of action. But, in some circumstances, our studies have been purely exploratory. Among our most successful findings have been:

  1. Alkylating agent plus purine analogs (cytoxan & fludarabine)
  2. Platin plus antimetabolites (cisplatin & 5FU; cisplatin & gemcitabine)
  3. Dual antimetabolite combinations (gemcitabine & capecitabine)
  4. Natural products plus anti-metabolite (Doxil & gemcitabine; vinorelbine & capecitabine)

More recently, we have explored the interaction between signal transduction inhibitors. The results of these investigations have been the subject of numerous presentations at international meetings.

The application of synergy analyses may represent one of the most important applications of our functional profiling platform; enabling us to explore both anticipated and unanticipated favorable interactions. Equally important may be our capacity to study drug antagonism wherein two effective drugs counteract each others’ benefits. This phenomenon, characterized by the whole being less than the sum of the parts, represents a major pitfall for clinical trialists who simply combine drugs “because they can.”

These analyses are revolutionizing the way our group applies newer classes of drugs and has the potential to accelerate drug development and clinical therapeutics. Good outcomes require good drugs, but better outcomes require good combinations. Intelligent combinations are a principle focus of the work at Rational Therapeutics. We strive everyday to identify the best outcomes for patients.

National Cancer Institute Stops Gene-based Clinical Trials – Part 2

Last week we discussed the National Cancer Institute’s suspension of three ongoing clinical trails using genomic platforms to select therapies for cancer patients. This week, we seek to answer the question: What went wrong?

The simple answer is that cancer isn’t simple.

Cancer dynamics are not linear. Cancer biology does not conform to the dictates of molecular biologists. Once again, we are forced to confront the realization that genotype does not equal phenotype.

In a nutshell, cancer cells utilize cross talk and redundancy to circumvent therapies. They back up, zig-zag and move in reverse, regardless of what the sign posts say. Using genomic signatures to predict response is like saying that Dr. Seuss and Shakespeare are truly the same because they use the same words. The building blocks of human biology are carefully construed into the complexities that we recognize as human beings. However appealing gene profiling may appear to those engaged in this field (such as Response Genetics, Caris, the group from Duke and many others) it will be years, perhaps decades, before these profiles can approximate the vagaries of human cancer.

Functional analyses like the EVA-PCD platform, which measure biological signals rather than DNA indicators, will continue to provide clinically validated information and play an important role in cancer drug selection. The data that support functional analyses is demonstrably greater and more compelling than any data currently generated from DNA analyses.

The Rational Difference

Truly Personalized Cancer Care

In the mid 1980s, it became apparent to me that cancer did not result from uncontrolled cell proliferation, but instead from the lack of cell death. Yet, cancer research labored for almost a century under the erroneous belief that cancer represented dysregulation of cell proliferation. Today, we confront another falsehood: the complexities and redundancies of human tumor biology can be easily characterized based on genomic analyses.

The process of carcinogenesis reflects the accumulation of cellular changes that provide a selective survival advantage to transformed cells.  However, the intricate circuitry that provide these survival advantages, reflect harmonic osolations between DNA, RNA and protein. Put simply, Genotype does not equal Phenotype. It is the phenotype that determines biological behavior and clinical response in cancer. Thus, it is ridiculously simplistic to imagine that a DNA profile by itself can provide more than a fraction of the information required to make individual patient treatment decisions.

When therapies are based on genomic analysis, only a portion of the patient’s profile is taken into consideration. These analyses disregard the environmental, epigenetic and proteomic factors that make each of us individuals. Though useful prognostically and applicable in select circumstances where a unique genetic perturbation leads to a clinical response (c-ABL and Imatinib response in CML), genomic analyses provide only a veneer of information.

The Rational Therapeutics Ex Vivo Analysis – Programmed Cell Death™ (EVA-PCD) assay focuses upon the complexity of human tumors by measuring cell death, the end result of all cellular mechanisms of response and resistance acting in concert. By incorporating cell-cell, vascular, stromal and inflammatory elements into the tumor response assessment, the EVA-PCD platform provides a robust surrogate for human tumor response. While much of modern cancer research pursues the question of “Why” cancer arises, the clinical oncologist must confront the more practical question of “How” the best outcome can be achieved.

Assay-directed therapy is truly personalized cancer care providing treatments unique to the individual.