Future Cancer Shock: Two Lung Cancer Trials Fall Short of Goal

Two related clinical trials were reported in the last several months describing the use of heat shock protein 90 (HSP90) inhibitors in lung cancer. Both trials fell short of their pre-specified endpoints casting a pall upon these drugs. However, the study of HSP90 inhibitors should not be abandoned based on these finding, as this is a fertile area of investigation and offers opportunities for the future.

Human cells marshal many defenses against stress. Thermal injury can damage basic cellular functions by denaturing (inactivating) proteins. The machinery of cells is largely comprised of protein enzymes. Excessive heat coagulates proteins much the same way the albumin of an egg turns white during cooking. The loss of fluidity and function ultimately results in cell death. The heat shock proteins come to the rescue by shepherding these proteins away from injury and protecting them from denaturation. There are many different heat shock proteins found in human cells, but one of the most abundant and active in cancer cells is known as HSP90 for its molecular weight in the range of 90-kilodaltons. Over the last two decades, investigators have explored the use of small molecules to inhibit these important proteins. Among the first compounds to be isolated and applied were derivatives of Geldanamycin. Although Geldanamycin itself is a poison that causes severe liver damage, its derivative 17-AAG, also known as Tanespimycin, has successfully entered clinical trials.

The current studies examined two other HSP90 inhibitors. One Retaspimycin, has been developed by the Infinity Pharmaceuticals. This clinical trial combined Retaspimycin with Docetaxel and compared results with Docetaxel alone in 226 patients with recurrent lung cancer. None of the patients had received Docetaxel prior to the trial. Drugs were administered every three weeks and the efficacy endpoint was survival with a subset analysis focused upon those with squamous cell cancer. The trial fell short of its pre-designated endpoint. Interestingly, the study failed to provide benefit even in patients who were specifically targeted by their tumor’s expression of the K-RAS, p53 or by elevated blood levels of HSP90, the putative biomarkers for response.

The second trial examined a different HSP90 inhibitor developed by Synta Pharmaceuticals. The drug Ganetespib was combined with Docetaxel and the combination was compared with Docetaxel alone. The results just reported indicate that the combination provided a median survival of 10.7 month, while Docetaxel alone provided a median survival of 7.4 month. Although this represented a three-month improvement, it did not meet the pre-specified target.

Taken together these results could dampen enthusiasm for these agents. This would be unfortunate, for this class of drugs is active in a number of human tumors.

Through our EVA-PCD functional profile we have observed favorable activity and synergy for the HSP90 inhibitor Geldanamycin and its derivative 17-AAG as we reported at the American Association for Cancer Research meeting in 2005 (Nagourney RA et al Proc. AACR, 2005). More importantly, 17-AAG (Tanespimycin) provided objective responses in 22 percent and clinical benefit in 59 percent of patients with recurrent HER2 positive breast cancer after these patients had failed therapy with Herceptin (Modi S. et al, Clinical Cancer Research August 2011). This clearly supports the role of HSP90 inhibition in breast cancer and would suggest that other more carefully selected target diseases could benefit as well.

The function of HSP90 is not completely understood as it influences the intracellular trafficking of dozens of proteins. One of the complexities of this class of drugs is that they protect and enhance the function of both good and bad proteins. After all, the HSP90 protein doesn’t know which proteins we as cancer doctors would like it to protect.

When we apply EVA-PCD analysis to these and other related classes of compounds, we focus our attention upon the downstream effects, namely the loss of cell survival. That is, whatever proteins are influenced, the important question remains “did that effect cause the cells to die?”

Classes of compounds with nonspecific targets like the HSP90 inhibitors will surely be the most difficult to characterize at a genomic or proteomic level: What protein? What gene? Functional platforms like the EVA-PCD offer unique opportunities to study these classes of agents. We are convinced that the HSP90 inhibitors have a role in cancer therapy. It would be unfortunate if these setbacks led us to “throw the baby out with the (hot) bathwater,” thus, slowing or preventing their use in cancer treatment.

The Molecular Origins of Lung Cancer

I had the luxury of attending the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; Biology, Therapy and Personalized Medicine held in San Diego earlier this month. I say luxury, for as my schedule closes in on me and I sometimes find myself working 13-hour days, it can be difficult to take even a couple of days away to attend meetings. But this conference was too good to pass up (hats off to Marge Foti and all the AACR staff for all their great work).

This symposium organized by David Carbone and Roy Herbst, brought together a broad spectrum of sophisticated scientists and international investigators, as well as community members and fundraising organizations who had the opportunity to present a special session on patient advocacy.

The meeting began with a keynote address examining microRNAs and lung cancer presented by Frank Slack from Yale University. He examined the growing recognition that lung cancer arises not only from gene mutations but also from small fragments of RNA that can up- or down-regulate normal genes in abnormal ways. This was the topic of discussion for many subsequent presentations.

As an aside, many of the readers will know that I am generally underwhelmed by genomic analyses for the prediction of cancer response. The fact that normal genes can function abnormally under the control of these small RNA sequences is just one more example of the genotype–phenotype dichotomy that cannot be adequately examined on static contemporary genomic platforms.

Many presentations examined the molecular biology of lung cancer with important distinctions being drawn between adenocarcinoma and squamous cell carcinomas. While adenocarcinomas reveal a growing number of targets – EGFR, ALK, ROS, RAS, and others – all the subject of small molecule inhibitors; squamous cell carcinomas provide fewer opportunities for the use of these classes of drugs.

One of the interesting discussions was the frequent mutation of LKB1 in lung cancers. Work going back several years by John Minna, a pioneer in this field, identified changes in this metabolic regulator as a common finding in lung malignancies.

Additional presentations examined chemoprevention, molecular pathology, new mechanisms to categorize lung cancer subtypes, and a very interesting discussion of field cancerization. In a particularly interesting analysis, Ignacio Wistuba from M.D. Anderson, showed that molecular changes in the surface epithelium of the lung bronchioles recapitulated the molecular biology of the final tumor in a step-wise manner, inversely related to the distance to the tumor. That is, starting at the main bronchi, one or two mutational changes were detected. Moving closer to the site of the tumor, additional mutations were accumulated. Finally arriving at the site of the established malignancy, all of the constituent mutations associated with this particular cancer became manifest; a saltatory slide into cancer presumably associated with exposure to carcinogens.

Among the other exciting presentations were updates on redox-based approaches to cancer presented by Kenneth Tew and Garth Powis.

Jeff Engelman presented an update on a new class of agents that target the RAS pathway. This is ongoing work that he and his group have reported on over the last several years. We have been engaged in related work using an MEK/ERK inhibitor similar to the compound that Dr. Englemen reported on at this meeting. It is exciting indeed to see early clinical results with this class of compounds, for we have identified many patients who might benefit from this pathways’ inhibition. We wait with great anticipation for FDA approval of these compounds so that our patients currently being identified as candidates in the laboratory may soon receive these treatments.

Recurrent Small Cell Cancer of the Lung: A Therapeutic Challenge

I recall as a junior medical oncology Fellow, one of my senior Fellows describing small cell cancer of the lung as “leukemia of the lung.” The reason he used this description was because leukemia is among the most rapidly progressive and aggressive forms of cancer.

Arising in the bone marrow, an afflicted patient’s white blood cell count can double every day, a remarkable achievement when one considers the hundreds of billions of cells involved. What this doctor meant was that the lung cancer of small cell type (also known as oat cell), grew so rapidly that in untreated patients, survival can be measured in weeks to months. With the discovery of effective chemotherapy this disease became a comparatively easy mark for the treating oncologist. Ironically, where it was the worst form of lung cancer during the 70s, by the 1990s it was the best form to have. Most patients responded to treatment and some lived years. The problem is, treating patients who recur.

For unknown reasons this otherwise chemosensitive disease has a tendency to recur with a vengeance. Attempts to control recurrent disease with second line therapies have characteristically been unsuccessful. Drug combinations that are generally quite active in the first line setting, are almost universally inactive in second line use.

As a result, recurrent small cell lung cancer is tantamount to a death sentence.

Two months ago, a slender woman arrived at Rational Therapeutics carrying a biopsy kit and a bottle filled with straw-colored fluid. She explained that her husband had recurrent small cell lung cancer and his surgeon had inserted a chest tube. He then provided us with both biopsy material and fluid. She went on to say that she herself was a laboratory scientist and was familiar with laboratory techniques.

We processed the specimen, which provided amble cells for analysis. Not surprisingly, the tumor was resistant to many (most) of the drugs tested. However, the class of drugs known as alkylating agents revealed persistent activity. More importantly, the combination of an alkylating agent and topotican revealed activity and synergy.

Having published a paper on this topic several years ago, (Nagourney et al, British Journal of Cancer 2003) I was quite familiar with this combination. Referencing work by investigators at Yale University, using the combination of cytoxan and topotican, I provided my recommendation to a colleague who administered this combination with a very tolerable weekly dose schedule.

The patient responded immediately. So much so, that between cycle one and cycle two he took a vacation to San Diego with his wife.  Further response was documented following cycle two.  Most gratifying has been the very limited amount of toxicity in the treatment itself.