Two Lung Cancer Trials Fall Short of Goal

[gpawelski]

Robert A. Nagourney, M.D.

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 findings, 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.

http://www.ncbi.nlm.nih.gov/pubmed/23580070

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.

http://meetinglibrary.asco.org/content/112583-132

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.

[gpawelski]

Heat-shock factor reveals its unique role in supporting highly malignant cancers

Whitehead Institute researchers have found that increased expression of a specific set of genes is strongly associated with metastasis and death in patients with breast, colon, and lung cancers. Not only could this finding help scientists identify a gene profile predictive of patient outcomes and response to treatment, it could also guide the development of therapeutics to target multiple cancer types.

The genes identified are activated by a transcription factor called heat-shock factor 1 (HSF1) as part of a transcriptional program distinct from HSF1's well-known role in mediating the response of normal cells to elevated temperature. In normal cells, a variety of stressors, including heat, hypoxia, and toxins, activate HSF1 leading to increased expression of so-called heat-shock or chaperone proteins that work to maintain protein homeostasis in stressed cells.

Scientists have known for some time that many cancer cells have higher levels of chaperones and that elevation of these proteins is important for survival and proliferation of tumor cells. Now, however, researchers in the lab of Whitehead Member Susan Lindquist report that HSF1 supports cancers not only by increasing chaperones, but by unexpectedly regulating a broad range of cellular functions that are important for the malignant behavior of tumor cells.

This activity allows for the development of the most aggressive forms of three of the most prevalent cancers, breast, lung, and colon. The findings, published this week in the journal Cell, build on earlier research from the Lindquist lab showing that elevated levels of HSF1 are associated with poorer prognosis in some forms of breast cancer. "This work shows that HSF1 is fundamentally important across a broad range of human cancers, cancers of various types from all over the body turn on this response," says Sandro Santagata, a postdoctoral researcher in the Lindquist lab. "That's very interesting. It suggests how important HSF1 must be for helping tumors become their very worst."

In addition to confirming that this gene activation program differs from that associated with heat shock, the researchers found that in many tumors, it becomes active in virtually all of the tumor's cells. "This demonstrates it isn't simply regions of microenvironmental stress within a tumor that drive HSF1 activity, but rather that HSF1 activation is wired into the core circuitry of cancer cells, orchestrating a distinct gene regulatory program that enables particularly aggressive phenotypes," says Marc Mendillo, a postdoctoral researcher in the Lindquist lab. "This suggests HSF1 itself could be a great therapeutic target."

Luke Whitesell, an oncologist and senior research scientist in the Lindquist lab, concurs that HSF1 is a conceptually appealing target for therapeutic intervention, noting that suppressing HSF1 for short periods of time should have minimal consequences on normal cells.

However, he adds, actually developing such a drug could be problematic. "Coming up with a drug that disrupts HSF1's interaction with DNA, which is how it activates all of these genes, that is going to be really tough," says Whitesell. "No one has come up with a clinically useful drug that directly interrupts a transcription factor's interaction with DNA yet. But there are ways to disrupt a transcription factor's function indirectly, as opposed to directly targeting the protein itself. What we have now from this research is a new view of the landscape and the possibilities for drug discovery and development that are out there."