New Cancer Drug: Breakthrough or Just Hype?

Having just passed through Ontario’s Pearson International airport on route from eastern Canada, I was struck by an email from one of my patient’s mothers who shared with me a 6/20/2013 article from the Toronto Globe and Mail, “Take news of cancer breakthrough with a big grain of salt,” by staff writer André Picard.

The author describes an announcement by two prominent cancer researchers, Tak Mak, PhD, of Princess Margaret Hospital Toronto, CA and Denis Slamon, MD, from UCLA, who reported the results from a new class of compounds known as “polo-like kinase 4 inhibitors.” Picard goes on to note, “This seemingly miraculous ‘breakthrough’ drug has not been tested on a single person. The experimental drug CFI-400945 has ‘prevented cancer growth’ in a bunch of mice.”

What troubles the author (and should probably trouble us all), is the lack of substance in this report. After all, many drugs reveal activity in animal models, yet most seemingly promising drugs fail to provide clinical benefit. Only 8 percent of cancer chemotherapy drugs that enter the earliest form of human clinical trials (Phase I) ever achieve FDA approval. According to a study published in the New England Journal of Medicine, fully 50 percent of drugs that make it to the final stage (Phase III) of clinical testing nonetheless fail to gain approval. Thus, there is ample reason for concern when “breakthrough” drugs achieve this level of public recognition, because it is distinctly unlikely that they will ever deliver on their promises.

When I attend the AACR meetings, I’m impressed by the level of scientific discovery. When I then attend the ASCO meetings, I’m even more concerned by the lack of clinically relevant progress. The divide between clinicians and scientists seems to grow ever wider. While TIME magazine and The New York Times (to use Andre Picard’s term) genuflect before these scientists’ reports of dramatic advances, most cancer patients continue to suffer through largely ineffective toxic therapies. The disconnect is becoming painfully evident. What we need is a better pathway from discovery to clinical application. What we don’t need is more hype.

What Exactly are the Targets of Targeted Therapy?

The term “targeted therapy” has entered common parlance. Like personalized medicine, targeted therapy is a generic description of drugs and combinations that inhibit specific cancer-related pathways. I am impressed by how quickly esoteric phenomena like the downstream signal in the insulin factor pathway have entered the lexicon of medical oncologists. With the advent of temsirolimus and everolimus, both rapamycin derivatives that target mTOR, we now have at our disposal agents that are every bit a part of the therapy repertoire. Unlike erlotinib that targets a specific tyrosine kinase, mTOR is a complex and multifaceted target.

There are actually two separate forms of mTOR, TORC1 and TORC2, and they sit at a critical point in cellular determination. Stimulated by the insulin growth pathway, cells must decide whether they will grow in size or divide. The mTOR proteins participate in this process by regulating protein synthesis and glucose uptake among other functions. In turn, the mTOR pathway is regulated by numerous other factors like AMP kinase and AKT. The current crop of mTOR inhibitors all target TORC1.

New classes of compounds are being developed that inhibit both TORC1 and TORC2. More interesting are the compounds that influence upstream signaling, including phosphoinositol kinase (PI3K) and AKT. What we are coming to learn, however, is that these are not targets but collections of targets. Indeed, the PI3K inhibitors themselves have influence on one, two or all of the distinct classes of phosphoinositol kinases.

Most of the studies to date have used compounds that affect all the classes equally (pan-inhibitors). Pharmaceutical companies are now developing highly selective inhibitors of this fundamental pathway. In addition, duel inhibitors that target both PI3K and mTOR are in clinical trials. What we are coming to realize is the complexity of these pathways. What may prove more vexing still is their redundancy. One well-established by-product of successful inhibition of mTOR (principally TORC1) is the upstream activity of AKT via a feedback loop. This has the undesirable affect of redoubling mTOR stimulation through the very pharmacological manipulation that was designed to inhibit it. Again, an unintended consequence of a well laid plan.

To unravel the complexities and redundancies of these processes, we have utilized the primary culture platform. It enables us to examine the end result of signal inhibition and dissect disease specific profiles. Using this approach we can partner with collaborators to define the specific operative pathways in each disease entity.

Biological complexity is the hallmark of life. We ignore it at our peril.

Cancer Research Becomes “Curiouser and Curiouser”

Following the Gina Kolata New York Times article on July 8, 2011, which described the failure of the Duke University gene profile program in lung cancer, a second New York Times article popped up on the radar screen.  “Cancer’s Secrets Come into Sharper Focus” by George Johnson, examined the growing complexity of cancer research.

This article explored the growing realization that human biology is not linear. Included were references to work that we have previously described in this blog, including the groundbreaking work of Pier Paolo Pandolfi. It also described the interaction between the human body and its microbial flora. We have long recognized that human health is, in part, associated with our interaction with microbes in our environment. The gastrointestinal tract has numerous species that are increasingly believed to contribute to our health. The growing field of probiotics, wherein people consume “healthy organisms,” has gone from quackery to community standard in less than a decade.

What is interesting over the past years is the growing recognition that many cancers are related to infections. Viral infections are known to be oncogenic, with the Epstein-Barr virus, HPV and other viruses now known to be causative of lymphomas, cervical, head and neck, and other cancers. The association between helicobacter and ulcers, gastric lymphoma, and esophageal malignancies are of interest both epidemiologically and therapeutically.

What is most interesting of all is the growing recognition that the cancer cell is but a small component of the cancer.

Here at Rational Therapeutics we recognized the interplay between cells, stroma, vascular elements, cytokines, macrophages, lymphocytes and other environmental factors. This lead to our focus on the human tumor primary culture microspheroid, which contains all of these elements. In our earlier work, we endeavored to isolate tumor cells from their benign constituents so as to study “pure” tumor cells. As time went on, however, we found that these disaggregated cells were artificially sensitized to the effects of chemotherapy and provided false positive results in vitro.

Early work by Beverly Teicher and Robert Kerbel that examined cells alone and in 3-dimensional structures, lead to the realization that cancer cells inhabit a microenvironment. Our lab now studies cancer response to drugs within this microenvironment, enabling us to provide clinically relevant predictions to our patients.

It is our capacity to study human tumor microenvironments that distinguishes us from other platforms in the field. And, it is this capacity that enables us to conduct discovery work on the most sophisticated classes of compounds that influence cell signaling at the level of notch, hedgehog and WNT, among other (Gonsalves, F, et al. (2011). An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of WNT/wingless signaling pathway. PNAS vol. 108, no. 15, pp. 5954-5963).  With this clinically validated platform we are now positioned to streamline drug development and advance experimental therapeutics.

The TEDx Experience

On Saturday July 16, I had the opportunity to present at the TEDxSoCal conference held here in Long Beach. The overall theme for this event was “thriving,” and appropriately, I presented in the afternoon session called, “well-being.” My lecture was entitled “The Future of Cancer Research Lies Behind Us.”

I chose this topic in light of the growing recognition that genomic analyses are not providing the therapeutic insights that our patients so desperately need. As I have written before in this blog, the Duke University lung cancer gene program, which has received much attention recently, is emblematic of the hubris associated with contemporary genomic analytic platforms.

I reviewed the contemporary experience in clinical trials, examined the potential pitfalls of gene-based analysis, and described the brilliant work conducted by biochemists and cell biologists, like Hans Krebs and Otto Warburg, who published their seminal observations decades before the discovery of the double helix structure of DNA.

I described insights gained using our ex-vivo analytic platform, that lead to treatments used today around the world, all of which were initially discovered using cell-based studies. More interesting still will be the opportunity to use these platforms to explore the next generation of cancer therapies – those treatments that influence the cell at its most fundamental level – its metabolism.

Many attendees stopped me after my lecture to thank and congratulate me for my presentation. Fearing that my topic might have been too esoteric, I was delighted by the reception and more convinced than ever that there are many enlightened individuals who thirst for new approaches to cancer treatment. It is these people who will forge the next generation of therapy.

American Association of Cancer Research (AACR) Meeting 2011

The Sunday, April 3, 2011, experimental and molecular therapeutics session at the AACR 102nd annual meeting included our presentation on signal transduction inhibitors. Using MEK/ERK and PI3K-MTOR inhibitors we explored the activities, synergies and possible clinical utilities of these novel compounds.

The findings were instructive. First, we saw a good signal for both compounds utilizing the Ex-vivo Analysis of Programmed Cell Death (EVA-PCD) platform. Second, we saw disease-specific activity for both compounds. For the MEK/ERK inhibitor, melanoma appeared to be a favored clinical target. This is highly consistent with our expectation. After all, many melanomas carry mutations in the BRAF gene, and BRAF signals downstream to MEK/ERK. By blocking MEK/ERK, it appeared that we blocked a pathway fundamental to melanoma progression. Indeed, MEK/ERK inhibitors are currently under investigation for melanoma.

For PI3K inhibitors, the highest activity was observed in uterine cancers. This is interest, because uterine carcinomas are often associated with a mutation in the PTEN gene. PTEN is a phosphatase tumor suppressor that functions to block activation of the PI3K pathway. Thus, mutations in the tumor suppressor unleash PI3K signaling, driving tumors to grow and metastasize. Blocking PI3K provided a strong signal, indicating that this approach may be very active in tumors associated with these oncogenic events.

The third point of interest in our report was, perhaps, its most important. Specifically, that we can explore those diseases where MEK-ERK, PI3K and mTOR signaling are less established targets. Cancers of the lung, ovary, colon or breast all manifested profiles of interest. When we combined both pathway inhibitors in a process we call horizontal inhibition, renal cell carcinoma popped up as the best target. These results, though exploratory, suggest a superior approach for drug development, allowing us to identify important leads much faster than the clinical trial process.

The Role of Natural Products in the Treatment of Cancer

Cancer medicine utilizes small molecules as therapeutics. Many compounds in use today are derivatives of plant alkaloids. Among the most widely used drugs derived from plant alkaloids are the taxanes, vinca alkaloids and topoisomerase inhibitors. Antibiotic anti-tumor agents including anthracyclines, Bleomycin and Mytomycin-C have been isolated from streptomyces bacterial cultures. Several antimetabolites also have their origins in natural products.

It is evident that nature is an excellent source of effective treatments. Unfortunately, there has been hesitancy on the part of the conventional oncology community to incorporate other natural products into therapeutics. Nonetheless, a wide variety of plant extracts have significant anti-tumor activity. Among the compounds under investigation are the cyclic triterpenes, mono- and di-terpenes, as well as stilbenes and derivatives of scutellaria and glyzrrha. In addition to cytotoxic activity, many plants are effective in chemoprevention. Extracts of grape (resveratrol), chocolate, green tea (catechins), as well as colored fruits (anthocyanins) and berries (ellagic acid) can elicit protective responses, some mediated by the KEAP-1, NRF-2 pathway. Click here to read a previous article that discusses the medicinal qualities of garlic, wine and chocolate.

The arbitrary distinction between commercial therapeutics and nutritional substances has created an unnecessary barrier between conventional therapists and those who practice complimentary care. A growing cadre of physicians is developing expertise in natural product therapeutics in parallel to their traditional training. Chinese herbal and Indian ayurvedic medicine instruct physicians in the appropriate use of natural therapies. An explosion of interest in resveratrides, curcuminoids and terpenes are fueling a rebirth of interest in these naturopathic approaches.

As an editor of the Journal of Medicinal Food, I have contributed to the literature on the medicinal value of foodstuffs and natural products. Original articles on the benefits of garlic have been followed by the study of the monoterpene limonene and contributions on Chinese herbal medicines, chocolate extracts and grape seed extracts. Our laboratory has been engaged in the formal analysis of many natural products and we have reported exciting results with several classes of compounds. In one instance, an Australian extract was administered successfully in the treatment of advanced renal cancer under FDA IND. We are convinced that an exciting opportunity for cancer treatment exists in the formal study and rigorous evaluation of these biologically active molecules and combinations.

Horizontal and Vertical Signal Pathway Inhibition

The importance of signal pathway inhibition in human tumor primary culture microspheroids.

Signal transduction pathways are important targets in cancer therapy. Small molecule inhibitors for the tyrosine kinase and serine threonine kinase pathways are already available for clinical therapy. Additionally, compounds targeting the PI3K, AKT and MEK pathways will be available in the coming years. To explore the interaction of these parallel survival pathways, we compared activity and combined these inhibitors in human tissues — the results were instructive.

Our findings include favorable interactions between EGFr tyrosine kinase inhibitors and compounds that block the PI3K pathways. The most active combinations were those that inhibited the cross-talk between pathways (horizontal inhibition) over drug combinations that targeted the same pathway at different downstream points (vertical inhibition). Similar observations have been made combining PI3k inhibitors and MEK inhibitors. One such report in PNAS (May 10, 2010) closely paralleled the work conducted in our laboratory, Rational Therapeutics, that we reported at the AACR.

Noteworthy, a series of studies utilizing these combinations, indicate that certain tumors respond to their drug exposure by undergoing autophagic death, not necrotic or apoptotic. This distinction is possible, as the Ex-Vivo Analysis of Programmed Cell Death (EVA-PCD®) platform has the capacity to measure all forms of cell death – apoptotic and non-apoptotic.

We continue these studies in numerous solid tumors to explore those diseases that will be the best candidates for these types of combination therapies. Please leave a comment below if you would like more information on these studies.