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.

Ovarian Cancer National Alliance 2011

The July meeting of the OCNA included a lecture by John Hays, MD, from the National Cancer Institute (NCI), entitled “Decision time: what is the right choice of chemotherapeutic agent(s)? Dr. Hays, part of the molecular signaling section at the NCI, reviewed literature on the topic. He described the need for prospective clinical trials to validate retrospective and in vitro results.

He then examined data from three technologies, the Oncotech extreme drug resistance test, Precision Therapeutics ChemoFX test and the ATP-based chemosensitivity test.

I found it odd that Dr. Dr. Hays spent time examining the EDR technology of Oncotech in as much as it is no longer offered and reflects proliferation-based studies, which have since largely been discredited.

The ATP assay was reviewed using the results of a study published by Dr. Ian Cree in which 180 patients received either assay-directed (ATP) or physician choice. This study actually provided an improvement for patients who received the ATP-based treatment but failed to achieve significance. Thus, it failed largely because it was underpowered.

But this reflected a more concerning aspect of the study.  It seems that the “physician choice” arm increasingly applied the best drug regimens developed in Dr. Cree’s own laboratory. As the trial continued to accrue, an increasing proportion of patients received Gemcitabine-based doublets (which were very new at the time) based upon Dr. Cree’s observation of activity for these novel combinations. This had the uncomfortable effect of forcing Dr. Cree to compete with himself. Had Dr. Hays been truly interested in examining this study as I have, he might have noticed the good control group response rate partly reflected the application of Dr. Cree’s’ own observations.

Indeed, when during my many attempts to conduct a prospective study with the GOG, I was at the very last moment confronted with a study design similar to Dr. Cree’s, (e.g. they could incorporate any treatment they chose, including those that I developed), my statistician demanded that I forego the pleasure, as he could see only too well that the trial had become impossible to power. You see, there was no true control arm for statistical comparison.

The final portion of Dr. Hays’ presentation was the ChemoFX assay. This technology propagates tissue biopsies to confluence and then conducts measurement of drug-induced cell death. With substantial funding largely provided by venture capital, Precision Therapeutics has leapt into the GOG with a series of trials. Should this hybrid technology fail to provide prospective results that meet significance, it will be a damaging blow to this unfairly maligned area of investigation. While I wish the ChemoFX investigators luck, a failure on their part could be harmful to the field. Their reliance on propagated, sub-cultured tissues grown to monoculture has been a concern to me since they first arose in the last few years as participants in the field. We await the results of their trials with great anticipation.

What is interesting in Dr. Hays’ review is not so much what he said, but what he didn’t say.

First, he did not mention the seminal work of Dr. Larry Weisenthal, a pioneer in the field.

Second, he did not describe the nearly 2,000 retrospective, yet statistically significant correlations in the literature in a wide variety of diseases. He neglected to mention that one of the most widely used regimens for breast and ovarian cancer was developed using the same human tumor culture analyses that he decries. If he actually treats patients, he no doubt uses the cisplatin gemcitabine doublets developed using one of these platforms.

Finally, Dr. Hays has failed evidence-based medicine 101. He has forgotten that in life-threatening illnesses where prospective clinical trial data is not available, in accordance with the dictates of evidence-based medicine, one should use the best available data to guide treatments.

There is a wealth of data supporting laboratory based drug selection.  Presentations like that described do not add to the discourse.

Is There a Role for Maintenance Therapies in Medical Oncology?

There is a long tradition of maintenance therapy in pediatric oncology. Children with acute lymphoblastic leukemia uniformly receive three stages of therapy: induction, consolidation, and finally maintenance. The maintenance stage consists of weekly, or even daily therapies.

The historical experiences of relapse in this population lead investigators to consistently expose these patients to drugs for a period of years. Despite the apparent success of this approach in childhood cancers, long-term maintenance therapy did not gain popularity in adult oncology. Why?

There are probably several reasons. One reason is that childhood leukemia is among the most chemo-responsive diseases in medicine. As such, there are many active drugs available for treatment and many non-cross-resistant maintenance schedules that can be employed.

A second reason is the relative tolerability of drugs like oral thioguanine or mercaptopurine that are used in chronic maintenance therapy. By contrast adult tumors rarely achieve complete remissions. The number of active drugs has historically been very limited and the tolerance of long-term treatments characteristically poor.

Despite this, there is an appealing rational for maintenance therapy. Once we recognized and incorporated the tenents of apoptosis and programmed cell death into cancer management, we were forced to reconsider many of the principles of older treatment protocols.

Conceptually, maintenance allows for a cytotoxic exposure when the cell enters a “chemosensitive” period in its life cycle.  Cancer cells that are “out surviving” their normal counterparts often do so in a quiescent stage (G0 Gx). In order to capture these cells, drugs must be present in the body when these cells awaken from their dormancy. As we have now achieved increasingly durable remissions in diseases like breast cancer, small cell lung and ovarian, we are confronting patients in long-term complete remission. When you add to this newfound population the availability of comparably mild agents, like the low dose Gemcitabine/Cisplatin doublet, we now have at our disposal active drugs that can be safely continued for long periods of time.

Using laboratory selection to identify first line (induction), second line (consolidation) and finally third line (maintenance) schedules, we can now offer our patients well-tolerated combinations that offer the hope of more durable remissions.

The GOG 178, in which continued taxol dosing provided more durable remission in ovarian cancer, provided the first inklings of this. Unfortunately, taxol is toxic. And the more durable remissions came at an increasingly high price: neuropathy, myelosuppression, alopecia, fatigue and malaise, which greatly limited the utility of this approach. Yet it does not limit its theoretical attractiveness as we continue to develop targeted agents with more selective activity and modified toxicity profiles. We anticipate maintenance therapies will become more widespread.

Based upon our experiences to date, we are successfully using this approach with our patients who achieve good clinical remissions.

Lots of Heat No Light – ASCO Technology Assessment Update 2011

“Once more unto the breach, dear friends.”

This famous line from Shakespeare’s Henry V, describes the Battle of Agincourt and England’s unexpected victory over the French. Not unlike Henry V a small coterie of relatively underfunded and embattled investigators around the world continue to fight an entrenched medical community who refuse to relinquish their grip on the clinical trial process.

Their re-review updated from 2004, sheds no new light on the field, as the authors conclude that their 2004 recommendations stand without modification.

The authors, to their credit, have updated their database to include cell death endpoints. They cite the ovarian cancer study by Dr. Ian Cree, that assigned 180 patients, (of which 147 were evaluable), with recurrent disease, and reported a response rate of 40.5 percent for assay directed versus 31.3 percent for physician choice, yet failed to achieve significance. The reasons for this trial’s failure however were obvious, as it was underpowered and more importantly allowed the physician’s choice arm to include Dr. Cree’s own drug combinations as the trial accrued. This left Dr. Cree in the uncomfortable position of having to compete with himself.

More disturbing is their dismissal of a paper by Selma Ugurel, MD, from Clinical Cancer Research 2006 in which, patients with metastatic melanoma received assay-directed treatment for this otherwise chemo resistant and lethal disease. Patients found drug sensitive in the laboratory had a response rate of 36.4 percent, while those found drug resistant had a response rate of only 16.1 percent (a two-fold improvement). The overall survivals were similarly improved with assay-directed patients 14.6 months vs. drug resistant patients of 7.4 months. Again a doubling. Furthermore these results achieved statistical significance.

The ASCO group concludes with the comment, “However, the investigator did not compare the two interventions.” As I know this paper well, and was extremely impressed that some of the responders went out to 30 months, I find the ASCO group’s insouciance surprising.

This reminds me of an old joke by the comedian Jerry Seinfeld. It seems that he had watched a television program where a man caught bullets shot from a gun with his bare teeth. Seinfeld went on to say, that despite being immensely impressed by this man’s prowess, he just couldn’t seem remember his name. “What do you got to do to impress people”?

As I am familiar with the Ugurel paper, I have been very impressed with these investigators completing a study by dint of their dedication to the field. Stranded without funding or cooperative group support, laboratory-based therapeutics remains unconfirmed, not by the unwillingness of the investigators but by the unwillingness of the cooperative and funding agencies to test the hypotheses.

While we squander billions of dollars on genomic analyses that are increasingly leading us nowhere, these ASCO study groups and their colleagues continue to refuse to formally evaluate human tissue studies. In light of the lack of improvement in survival for most cancers over the past 50 years, despite the expenditure of hundreds of billions of dollars on research, perhaps assay-directed therapy is just the solution that medical oncology needs.