There is Nothing New Under the Sun

The most sophisticated Western medical centers, purveyors of allopathic medicine, spent decades denigrating natural products as “quackery.” Nutritional supplements, antioxidants and natural extracts were viewed as the purview of hippies and nuts. Yet, a brief examination of the most active compounds in cancer therapy today quickly establishes how wrong-headed this mindset was. In addition to the taxanes (extracts of taxus brevifolia and taxus baccata), the camptothecins (extracts of camptotheca acuminata), the vinca alkaloids and the epothilones, are host of simple small molecules like retinoids, platins and arsenic trioxide.

As Western scientists have developed a greater understanding of cellular circuitry and cancer metabolism, they have been dragged, kicking and screaming, to the admission that nature is indeed the best organic chemist.

Recent reports of a Chinese herb combination called PHY906 are but the latest example of this reality. Careful analysis reveals PHY906 — a combination of four herbs — contains 64 compounds including flavonoids, saponins and monoterpenes. As an editor of the Journal of Medicinal Foods, I have published and edited many articles on related topics. The terpenes are among the most important and ubiquitous bioactive compounds found in nature, with effects on cholesterol metabolism, Ras gene signaling, and mitochondrial function.

PHY906 is one more example of the adage that “there is nothing new under the sun.”

A Tale of Two Lung Cancers

I was recently asked to speak at a community outreach mixer to describe our work in lung cancer. I invited two patients to join me:

1. A woman in her early 50s who presented to medical attention with metastatic adenocarcinoma of the lung with brain involvement.
2. A woman in her early 60s, also with metastatic adenocarcinoma with brain involvement.

Under the microscope their tumors appeared almost identical. But, in the laboratory, the profiles were distinctly different. Patient no. 1 revealed a highly sensitive profile to the EGFR-TKI erlotinib (Tarceva) that was demonstrably enhanced by VEGF inhibition (e.g. Bevacizumab, Avastin). The second patient was resistant to erlotinib and VEGF inhibition, but was highly sensitive to the doublet of platinum plus gemcitabine.

Both patients attended the mixer and spoke to the crowd. They both looked the picture of health, sporting their own hair with no significant toxicities from therapy. Both had completed Cyberknife brain radiation and had gone on to exactly the right treatment for them. Despite their similarities in presentation and histology, their treatments were extremely different. Yet, both have had excellent and durable responses.

Every lung cancer patient has the capacity to do well. It is our job to find out which drugs and combinations are most likely to achieve that end. Functional profiling provided both of these patients exactly the right treatment for them. With the Rational Therapeutics EVA-PCD platform, every patient is treated as an individual.

Targeted Therapies — The Next Chapter

Within this blog, we have intermittently reviewed the concept of targeted therapies. To reiterate, these are classes of drugs that target specific pathways considered tumorigenic. Among the pathways initially targeted were the epidermal growth factor receptor and the closely related HER2. Shortly after the introduction of EGFr and HER2 directed therapies came the development of drugs that target another critical pathway, mTOR.

Hundreds of compounds are now under development intended to more accurately hone in on the pathways of interest in patients’ tumors. Regrettably, the medical community continues to apply old clinical trial methods to this newest era of drugs. While the selective application of drugs like: Tarceva for EGFR mutants, Herceptin for HER2 over-expressers, and Crizotinib for EML4-ALK mutants, are much more effective in patients with these gene expressions, these are a select few examples of linear thinking that bore fruit.

That is, this gene is associated with this disease state and can be treated with this drug.

Many, if not most cancers will prove to be demonstrably more complicated. Genomic trials can only succeed if we first know the gene of interest and second know that its (over) expression alone is pathogenetic for the disease entity. Even meeting these conditions is likely to result in comparatively brief partial responses due to the crosstalk, redundancy and complexity of human tumor signaling pathways — the “targets” of these new drugs.

To address these complexities, functional analytic platforms that examine outcomes, not targets, are needed. This bottom-up approach has now enabled my team to explore the activity of novel compounds. When investigators develop interesting “small molecules,” we examine the disease specificity, combinatorial potential and sequence dependence of these compounds in short-term cultures to provide meaningful insights that can then be addressed on genomic and proteomic platforms. This reduces the time required to take these new agents from bench to bedside. We cannot solve tomorrow’s questions using yesterday’s mindsets