The Future of Cancer Research

The American Association for Cancer Research meeting held April 6 – 10 in Washington DC, provided a scientific perspective on oncologic developments. As opposed to the more clinical American Society of Clinical Oncology (ASCO), basic scientists attend this meeting, a large percentage of who are PhDs. The conference affords these investigators the opportunity to discuss their basic research and to present methodology workshops. The meeting also provides an early overview of the general direction that cancer research will be taking over the coming years.

While ASCO reports what we’ve recently done, AACR reports what we will be doing.

There were several overarching themes at this year’s meeting, the most prominent of these being the remarkable strides in immunologic therapy. Numerous investigators reported novel developments in the field. Where the immune system used to present as an insurmountable barrier of complexity, today we have dissected specific response elements and immune suppressive pathways that offer unique opportunities for therapy. Immunologic therapeutics are now specializing into sub-domains.

One productive area reflects de-repression. The most mature example being ipilimumab, the monoclonal directed against CTLA-4. This broadly expressed T-cell repressor molecule can be de-repressed resulting in significant anti-tumor activity, but with moderate to severe toxicity. The inhibition of PDL-1 is more selective and therefore less toxic, it has provided responses in melanoma, NSCLC and other diseases.

Earlier stage research is also focusing on tryptophan metabolism and the role of indoleamine 2, 3-dioxygenase. Manipulations of dendritic cells, altering prostaglandin TGF beta, IL-10, IL-6 and the STAT3 signaling pathway are also areas of active investigation. Additional studies included transferred receptors, like the CD19-related chimeric antigen receptor work and the targeting of co-stimulatory molecules like CD28.

Among the most striking observations in this field is the role of the human immune system and the tumor microenvironment in tumor promotion. Immunologists are rapidly learning that cancer is much more than just cancer cells.

The second broad concept that occurred repeatedly was the growing recognition of cancer as an organismal disease. When we realize that circulating tumor cells can be identified in the blood stream and bone marrow of virtually all cancer patients, even in many of those with putative in-situ disease, it becomes evident that invasive malignancies occur as the intersection of a primed cell and a receptive microenvironment. In light of our laboratory’s long held belief in the concept of native state microspheroids as predictive models (as used in our EVA-PCD® platform), this theme was highly appealing.

The developing principle that most closely approximated our work was captured in a special symposium organized by Charles Sawyer, president-elect of AACR. The topic of this well-attended session was the “N of 1.” That is, every patient is his or her own clinical trial. Nothing could be closer to our own work. During this session, two new directions for cancer research were described. The first, described as the “P2G,” was characterized by “exceptional responses.” The developing program through the NCI will collect tissue samples from patients who have had especially good responses from therapy and attempt to drill down on the mechanism of response. This exemplifies the phenotype to genotype (P2G). The second concept was the “G2P.” This reflects genomic screening, leading to the identification of lead targets followed by the administration of treatments. This “genotype to phenotype” approach is the one more closely aligned with investigations being conducted today at major centers here and abroad.

It is the exceptional response (phenotype to genotype) approach that most resonated. After all we have pioneered the field of phenotypic analysis. To wit, the use of human tissues in primary culture can offer the opportunity to explore literally dozens of exceptional responses in every patient’s tissues. A hit could provide insights for mechanistic discovery. It is my hope that this P2G paradigm will take hold – I see it as the most productive direction.

Why Oncologists Don’t Like In Vitro Chemosensitivity Tests

In human experience, the level of disappointment is directly proportional to the level of expectation. When, for example, the world was apprised of the successful development of cold fusion, a breakthrough of historic proportions, the expectations could not have been greater. Cold fusion, the capacity to harness the sun’s power without the heat and radiation, was so appealing that people rushed into a field about which they understood little. Those who remember this episode during the 1990s will recall the shock and dismay of the scientists and investors who rushed to sponsor and support this venture only to be left out in the cold when the data came in.

Since the earliest introduction of chemotherapy, the ability to select active treatments before having to administer them to patients has been the holy grail of oncologic investigation. During the 1950s and 60s, chemotherapy treatments were punishing. Drugs like nitrogen mustard were administered without the benefit of modern anti-emetics and cancer patients suffered every minute. The nausea was extreme, the bone marrow suppression dramatic and the benefits – marginal at best. With the introduction of cisplatin in the pre Zofran/Kytril era, patients experienced a heretofore unimaginable level of nausea and vomiting. Each passing day medical oncologists wondered why they couldn’t use the same techniques that had proven so useful in microbiology (bacterial culture and sensitivity) to select chemotherapy.

And then it happened. In June of 1978, the New England Journal of Medicine (NEJM) published a study involving a small series of patients whose tumors responded to drugs selected by in vitro (laboratory) chemosensitivity. Eureka! Everyone, everywhere wanted to do clonogenic (human tumor stem cell) assays. Scientists traveled to Tucson to learn the methodology. Commercial laboratories were established to offer the service. It was a new era of cancer medicine. Finally, cancer patients could benefit from effective drugs and avoid ineffective ones. At least, it appeared that way in 1978.

Five years later, the NEJM published an update of more than 8,000 patients who had been studied by clonogenic assay. It seemed that with all the hype and hoopla, this teeny, tiny little detail had been overlooked: the clonogenic assay didn’t work. Like air rushing out of a punctured tire, the field collapsed on itself. No one ever wanted to hear about using human tumor cancer cells to predict response to chemotherapy – not ever!

In the midst of this, a seminal paper was published in the British Journal of Cancer in 1972 that described the phenomenon of apoptosis, a form of programmed cell death.  All at once it became evident exactly why the clonogenic assay didn’t work. By re-examining the basic tenets of cancer chemosensitivity testing, a new generation of assays were developed that used drug induced programmed cell death, not growth inhibition. Cancer didn’t grow too much, it died too little. And these tests proved it.

Immediately, the predictive validity improved. Every time the assays were put to the test, they met the challenge. From leukemia and lymphoma to lung, breast, ovarian, and even melanoma, cancer patients who received drugs found active in the test tube did better than cancer patients who received drugs that looked inactive. Eureka! A new era of cancer therapy was born. Or so it seemed.

I was one of those naive investigators who believed that because these tests worked, they would be embraced by the oncology community. I presented my first observations in the 1980s, using the test to develop a curative therapy for a rare form of leukemia. Then we used this laboratory platform to pioneer drug combinations that, today, are used all over the world. We brought the work to the national cooperative groups, conducted studies and published the observations. It didn’t matter. Because the clonogenic assay hadn’t worked, regardless of its evident deficiencies, no one wanted to talk about the field ever again.

In 1600, Giordano Bruno was burned at the stake for suggesting that the universe contained other planetary systems. In 1634, Galileo Galilei was excommunicated for promoting the heliocentric model of the solar system. Centuries later, Ignaz Semmelweis, MD, was committed to an insane asylum after he (correctly) suggested that puerperal sepsis was caused by bacterial contamination. A century later, the discoverers of helicobacter (the cause of peptic ulcer disease) were forced to suffer the slings and arrows of ignoble academic fortune until they were vindicated through the efforts of a small coterie of enlightened colleagues.

Innovations are not suffered lightly by those who prosper under established norms. To disrupt the standard of care is to invite the wrath of academia. The 2004 Technology Assessment published by Blue Cross/Blue Shield and ASCO in the Journal of Oncology and ASCO’s update seven years later, reflect little more than an established paradigm attempting to escape irrelevance.

Cancer chemosensitivity tests work exactly according to their well-established performance characteristics of sensitivity and specificity. They consistently provide superior response and, in many cases, time to progression and even survival. They can improve outcomes, reduce costs, accelerate research and eliminate futile care. If the academic community is so intent to put these assays to the test, then why have they repeatedly failed to support the innumerable efforts that our colleagues have made over the past two decades to fairly evaluate them in prospective randomized trials? It is time for patients to ask exactly why it is that their physicians do not use them and to demand that these physicians provide data, not hearsay, to support their arguments.

Do We Already Have the Tools We Need to Cure Cancer?

The rapid-fire sequence of the annual American Association of Cancer Research (AACR) meeting, held in May, followed by the annual American Society of Cllinical Oncology (ASCO) meeting, held in June, provides the opportunity to put scientific discoveries into perspective as they find their way from theoretical to practical.

Members of AACR, the basic science organization, ponder deep biological questions. Their spin-offs arrive in the hands of members of ASCO as Phase I and Phase II trials, some of which are then reported at ASCO meetings.

Many of the small molecules my laboratory has studied over the years are now slowly making their way from “Gee Whiz” to clinical therapy. At the ASCO meeting I attended many of the Phase I sessions, where alphabet soup compounds had their first “in-human” trials. As most of these compounds are familiar to me, I was very interested in these early, though highly preliminary, results.

Departing from one Developmental Therapy (Phase I) session, with visions of signal transduction pathways in my head, I attended a poster discussion on triple negative breast cancer. For those of you unfamiliar with the term, it refers to an increasingly common form of breast cancer that doesn’t mark for the usual estrogen, progesterone, or HER-2 features. Often occurring in younger patients, this form of breast cancer can be aggressive and unresponsive to some forms of therapy. Much work has gone into defining sub-types of this disease and slow progress is being made.

As I examined the posters, one caught my eye, “Clinical Characteristics and Chemotherapy Options of Triple Negative Breast Cancer: Role of Classic CMF regimen. (Herr, MH et al, abstract #1053, ASCO 2012.) What these investigators showed in a series of 826 breast cancer patients was that those treated with the oldest drug combination for breast cancer (CMF) did better than those who received the more modern and more intensive anthracycline or taxane-based regimens. CMF, originally developed by Italian investigators in the 1970s, was the principal therapy for this disease for two decades before it was replaced, first by anthracycline and later by taxane-based treatments. What struck me was the unexpected superiority of this old regimen over its more modern, toxic and expensive brethren.

I began to wonder about other modern therapies and their real impact upon cancer outcomes. One study in HER-2 positive patients revealed relative equivalency between weekly taxol, every three-week Taxotere and Abraxane-based therapy. Once again, the cheaper, older, less toxic Taxol regimen proved superior. While most of the attendees at the ASCO meeting were considering how the newest VEGF inhibitor Regorafenib, or the addition of aflibercept, might impact their practices, I was somewhat underwhelmed by the results of these statistically significant, but clinically marginal survival advantages, all associated with great expense.

As I pondered the implications of the CMF results in triple negatives and those of the taxol results in HER-2 positives, I considered other old-fashioned therapies with newfound potential. Among them, losartan, the angiotensin antagonist that influences tumor stroma or the results of an earlier published study that identified intraconazole (a widely available anti-fungal therapy), as an inhibitor of the hedgehog pathway. While the pharmaceutical industry promotes the use of vismodegib, a hedgehog inhibitor for basal cell skin cancer, and dozens of trials examine VEGF and FGF inhibitors, I wondered whether losartan or intraconazole or other simple compounds and combinations might not already provide many of the tools we need. Is it possible that effective treatments for cancer are at hand?

Lacking the tools to decipher the signals and combine the agents to greatest effect, are we destined to continue to blindly administer increasingly expensive, toxic, yet arguably no more effective therapies? With the myriad of drugs and combinations available today, might it be that we “can’t see the forest for the trees.”

The False Economy of Genomic Analyses

We are witness to a revolution in cancer therapeutics. Targeted therapies, named for their capacity to target specific tumor related features, are being developed and marketed at a rapid pace. Yet with an objective response rate of 10 percent (Von Hoff et al JCO, Nov 2011) reported for a gene array/IHC platform that attempted to select drugs for individual patients we have a long way to go before these tests will have meaningful clinical applications.

So, let’s examine the more established, accurate and validated methodologies currently in use for patients with advanced non-small cell lung cancer. I speak of patients with EGFR mutations for which erlotinib (Tarceva®) is an approved therapy and those with ALK gene rearrangements for which the drug crizotinib (Xalkori®) has recently been approved.

The incidence of ALK gene rearrangement within patients with non-small cell lung cancer is in the range of 2–4 percent, while EGFR mutations are found in approximately 15 percent. These are largely mutually exclusive events. So, let’s do a “back of the napkin” analysis and cost out these tests in a real life scenario.

One hundred patients are diagnosed with non-small cell lung cancer.
•    Their physicians order ALK gene rearrangement     $1,500
•    And EGFR mutation analysis     $1,900
•    The costs associated $1,500 + $1,900 x 100 people =    $340,000
Remember, that only 4 percent will be positive for ALK and 15 percent positive for EGFR. And that about 80 percent of the ALK positive patients respond to crizotinib and about 70 percent of the EGFR positive patients respond to erlotinib.

So, let’s do the math.

We get three crizotinib responses and 11 erlotinib responses: 3 + 11 = 14 responders.
Resulting in a cost per correctly identified patient =     $24,285

Now, let’s compare this with an ex-vivo analysis of programmed cell death.

Remember, the Rational Therapeutics panel of 16+ drugs and combinations tests both cytotoxic drugs and targeted therapies. In our soon to be published lung cancer study, the overall response rate was 65 percent. So what does the EVA/PCD approach cost?

Again one hundred patients are diagnosed with non-small cell lung cancer.
•    Their physicians order an EVA-PCD analysis    $4,000
•    The costs associated: $4,000 x 100 people =    $400,000
•    With 65 percent of patients responding, this
constitutes a cost per correctly identified patient =     $6,154

Thus, we are one quarter the cost and capable of testing eight times as many options. More to the point, this analysis, however crude, reflects only the costs of selecting drugs and not the costs of administering drugs. While, each of those patients selected for therapy using the molecular profiles will receive an extraordinarily expensive drug, many of the patients who enjoy prolonged benefit using EVA/PCD receive comparatively inexpensive chemotherapeutics.

Furthermore, those patients who test negative for ALK and EGFR are left to the same guesswork that, to date has provided responses in the range of 30 percent and survivals in the range of 12 months.

While the logic of this argument seems to have escaped many, it is interesting to note how quickly organizations like ASCO have embraced the expensive and comparatively inefficient tests. Yet ASCO has continued to argue against our more cost-effective and broad-based techniques.

No wonder we call our group Rational Therapeutics.

Poster from Rational Therapeutics Lung Cancer ASCO Presentation

As I mentioned in a previous post, I recently presented “Phase II Trial of Personalized Chemotherapy In Stage IV NSCLC: Clinical Application of Functional Profiling in First-Line Therapy” (Abstract No. 7617; Citation: J. Clin Oncol 28:7s, 2010) at the 2010 ASCO Annual Meeting.

Following are shots of the poster that was presented. I encourage you to leave any comments and/or questions here as I would be pleased to respond to your inquiries.

Lung Cancer Response Rates Double – ASCO Presentation

On Sunday, June 6, 2010, I presented “Phase II Trial of Personalized Chemotherapy In Stage IV NSCLC: Clinical Application of Functional Profiling in First-Line Therapy” (Abstract No. 7617; Citation: J. Clin Oncol 28:7s, 2010) at the 2010 ASCO Annual Meeting. Colleagues received the presentation very well, with hundreds of attendees examining the findings.

The data are very exciting. This trial of 29 patients with metastatic (Stage IV) NSCLC achieved a response that was twofold higher than the national average (62 vs. 31 percent: p=0.0003). More striking was the 50 percent improvement of median time to progression (9.5 months vs. 6 months). And most exciting of all, the very excellent survival data with a median overall survival of 22.3 months compared with the national average of 12 months.

The most interesting aspect of this study is the fact that we utilized the very same chemotherapy drugs that are available to all medical oncologists in the United States. The trial was limited to FDA approved, compendium listed agents with specific indications for NSCLC. As such, we did not apply new classes of drugs, yet doubled the response rate and median overall survival.

The implications of this are staggering, particularly when we consider the impact that targeted agents are having on cancer care. I will explore these implications in the next entry when I discuss such agents.