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Expanding Cancer Targets


Cancer researchers have more options thanks to a growing number of cancer targets.

By Irena Melnikova

July 14, 2008 | The World Health Organization estimates that by 2020, there will be 16 million new cancer cases every year, and there is a continual need for novel therapies that will command premium pricing. In addition, as new medicines prolong life, some current short-term agents could see extended usage, thereby generating additional sales. These forces are driving the expansion of the global oncology market.

Despite the wealth of potential targets, current drugs address only a handful of the best-characterized oncogenesis pathways, but the number of targets is growing exponentially. While not all of these targets will work, several have the potential to improve efficacy for many tumor types, and contribute significantly to the oncology market over the next five years.

Protein & Proteasome Inhibitors
The network of interactions between proteins of the Bcl-2 family is critical for the regulation of cell survival and death. In cancer, anti-apoptotic proteins such as Bcl-2, Bcl-xL, Mcl-1, are often expressed at high levels, which leads to resistance to therapy and poor clinical prognosis. Bcl-2 contributes to the development of various B-cell malignancies, and the Bcl-2 family represents attractive targets. Combining Bcl-2 inhibitors with chemotherapy or radiation should sensitize tumors to conventional treatments and potentially overcome issues of resistance to traditional therapy. Companies developing small molecule inhibitors of the Bcl-2 proteins include: Abbott and Genentech; Infinity and Novartis; Ascenta Therapeutics; and Gemin X.

Molecular chaperones are required for proper folding of “client” proteins and their refolding under conditions of denaturing stress. For example, heat shock protein 90 (HSP90) is essential for maintaining the activity of proteins in the regulation of the cell cycle, cell growth and survival, apoptosis, and angiogenesis. Elevated levels of HSP90 occur in many cancers including breast, lung, colon, and brain. Targeting HSP90 could provide a unique way of blocking multiple pathways involved in tumorigenesis.

Companies developing HSP 90 inhibitors include Kosan and BMS; Infinity with MedImmune and AstraZeneca; Abraxis Biosciences; Biogen Idec (Conforma); Synta; Pfizer (via Serenex); and Vernalis and Novartis.

The proteasome is the heart of the cellular protein degradation system and proteasome inhibition results in accumulation of these proteins in the cell and subsequent cell death. Currently, Velcade (bortezomib, Millennium Pharmaceuticals) is the only proteasome inhibitor on the market. Despite its clinical successes, relapses are fairly common. Two new proteasome inhibitors are in clinical development—carfilzomib (PR-171, Proteolix), and NPI-0052 (Nereus). So far, carfilzomib-treated patients experienced no painful peripheral neuropathy (associated with Velcade). Improved tolerability could optimize dosing in a way that prevents the full recovery of proteasome activity after completion of dosing.

“Smart Drugs”
Several approaches to achieving high specificity, including conjugation of anticancer drugs to hormones, antibodies, and vitamin derivatives, are under intense investigation. Endocyte has focused on the development of receptor-targeted therapeutics based on folic acid. Tumor cells have greater dependence on folate than normal cells, and the folate receptor (FR) is over-expressed in many cancers, including ovarian, brain, kidney, lung, and breast carcinomas.

Endocyte’s proprietary linker technology allows conjugation of anticancer drugs to folate. Overall, this approach is supposed to dramatically increase the therapeutic index of potent anticancer drugs by significantly decreasing their dose-limiting toxicities through targeted delivery to tumor cells. Furthermore, the ability to optimize patient selection through the use of a companion diagnostic—an FR-imaging agent—could improve the probability of success of Endocyte’s approach compared to other cell-targeting strategies.

Improving Success
Oncology drug candidates have atrocious attrition rates. Approximately, 95% of anticancer drugs fail in clinical development—numbers that underscore the poor predictability of animal models in cancer drug development. Lesions that develop in a xenograft mouse often lose certain characteristics of the original human cancers, and inadequately reflect a given tumor’s heterogeneity. AVEO Pharmaceuticals (see, “The Billion-Dollar Model,” Bio-IT World, March 2004) has developed the Human Response Prediction platform for generating inducible in vivo cancer models for target identification, validation, and drug screening. The HRP platform produces tissue-specific tumors that contain relevant mutations found in human cancers in a mouse model. The resultant lesions even acquire spontaneous mutations—a process that mimics human tumors. AVEO’s models should be better predictors of human responses to anti-neoplastic therapy, increasing the probability of clinical success.

Irena Melnikova is a director with Leerink Swann. She can be reached at: irena.melnikova@leerink.com.

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This article appeared in Bio-IT World Magazine.

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