May 15, 2008 (Vol. 28, No. 10)

Irena Melnikova Ph.D.

Drugs Targeted at the Bcl-2 Family, HSP90, and the Proteasome Raise Hopes

According to the WHO, more than 11 million people are diagnosed with cancer annually, causing seven million deaths every year—roughly 12% of all deaths worldwide. WHO estimates that by 2020 there will be 16 million new cancer cases every year. The disease is the second leading cause of death in the U.S., exceeded only by heart disease.

In the U.S., the number of elderly people is projected to double between 2005 and 2030 from 36.5 million people to 72 million. Since about 76% of all cancers are diagnosed in people ages 55 and older, the burden of this disease is expected to rise in the upcoming years.

Although improvements in the diagnosis and treatment of cancer have increased the chances of surviving the disease, cancer remains a large unmet medical need. Even among the four most prevalent cancer types—breast, prostate, lung, and colon—mortality remains high, particularly for the latter two cancer types. Some cancers such as pancreatic, liver, and brain have virtually no therapeutic options that can produce longterm survival benefit, reflected by exceedingly high mortality numbers within the first year of diagnosis. Therefore, the demand for new therapies that could extend life expectancy and improve quality of life continues to rise.

Expansion of Oncology Market

The growing number of cancer patients and the need for novel therapies that will command premium pricing are expected to drive the expansion of the global oncology market. In addition, as new medicines increase survival and prolong life, some agents that are currently used for short periods of time could see extended usage, thereby generating additional sales.

Despite the wealth of potential targets that have been discovered as researchers increase their understanding of cancer, currently marketed drugs address only a handful of the best-characterized pathways. Although the number of targets pursued by drug development companies has been growing exponentially, not all these targets will work. Leerink Swann’s MEDACorp has identified several molecules that have the potential to improve efficacy for the majority of tumor types.

Bcl-2 Family

The establishment and maintenance of tumors relies in part on the ability of cancer cells to evade cell death or apoptosis. The network of interactions between antiapoptotic and pro-apoptotic proteins of the Bcl-2 family is critical for the regulation of cell survival and death. In human cancer, antiapoptotic proteins such as Bcl-2, Bcl-xL, Mcl-1 are often expressed at high levels, which leads to increased cell survival and resistance to therapy and poor clinical prognosis. Bcl-2 is known to be a contributing factor to the development of a number of B-cell malignancies. More recently, Bcl-2 along with Bcl-xL and Mcl-1 have been shown to be overexpressed in a number of solid tumors as well.

Therefore, Bcl-2 and other antiapoptotic proteins represent attractive targets for therapeutic intervention. Combining Bcl-2 inhibitors with chemotherapy or radiation is expected to sensitize tumors to these conventional treatments and potentially to overcome issues of resistance to traditional therapy. Several companies are developing small molecule inhibitors of the Bcl-2 proteins (Table 2).

Molecular chaperones are some of the most abundant cellular proteins. They are required for both the proper folding of other proteins (referred to as client proteins) upon synthesis and their refolding under conditions of denaturing stress. Heat shock protein 90 (HSP90) is a molecular chaperone that is essential for maintaining the activity of numerous client proteins involved in the regulation of cell cycle, cell growth and survival, apoptosis, and angiogenesis. Significantly, many HSP90 client proteins include those crucial for cancer-cell proliferation and survival.

HSP90 is known to be overexpressed in tumor cells compared to normal tissues from two to tenfold. Elevated levels of HSP90 have been documented in a variety of human cancers including breast, lung, colon, and brain. Collectively, these observations make HSP90 an attractive oncology target (Table 3).

Targeting HSP90 could provide a unique way of simultaneously blocking multiple pathways involved in tumorigenesis through the depletion of oncogenic factors essential for cancer cell proliferation and survival. Inhibition of HSP90 should lead to misfolding of client proteins, their destabilization, and the subsequent degradation by the proteasome-mediated pathway. Combination therapy of HSP90 inhibitors with other targeted agents and/or traditional cancer therapeutics might result in significantly enhanced efficacy especially in resistant tumors.

The proteasome is the primary component of the protein-degradation system in the cell and is involved in the regulation of a number of cellular processes including proliferation, survival, and apoptosis. Proteasome substrates comprise proteins involved in the regulation of the cell cycle, DNA repair, stress responses, apoptosis, as well as misfolded and misassembled proteins.

Proteasome inhibition results in accumulation of these proteins in the cell and subsequent cell death. The proteasome is a validated target for cancer therapy. Currently, Velcade® (Takeda Pharmaceuticals recently acquired the drug through its takeover of Millenium Pharmaceuticals), approved for the treatment of multiple myeloma and mantel cell lymphoma, is the only proteasome inhibitor on the market.

Despite the clinical successes of Velcade, a significant number of patients fall into the relapsed/refractory category. Inconvenient dosing (twice a week IV injection) and painful peripheral neuropathy limit Velcade use. Newer agents targeting the proteasome could potentially address these issues.

Two new proteasome inhibitors are currently in clinical development: carfilzomib PR-171 (Proteolix) and NPI-0052 (Nereus). Compared to Velcade, carfilzomib and NPI-0052 belong to distinct chemical classes, are irreversible inhibitors, and have different selectivities against the three proteolytic components of the proteasome. It is too early to tell though whether broad-spectrum inhibition or more selective proteolytic activity inhibition will result in better safety and/or efficacy profile for a proteasome-targeting agent.

Improving the Probability of Success

The concept of targeted therapies for cancer emerged from the desire to provide highly effective treatments that would have minimal side effects. Conventional chemotherapeutics kill rapidly dividing cells by acting on the cell-division process. Unfortunately, in addition to killing tumor cells, chemotherapy also destroys normal cells.

A potential solution to current chemotherapy limitations would be to deliver anticancer agents to the tumor tissues with high specificity, thereby sparing normal cells. Several approaches to achieving a high degree of specificity, including conjugation of anticancer drugs to hormones, antibodies, and vitamin derivatives, have been investigated by the industry.

Oncology drugs candidates have one of the highest attrition rates in the industry. Approximately 95% of anticancer drugs fail in clinical development. Among other factors, these numbers underscore the poor predictability of animal models.

Human cancer xenografts, a present-day labortory standard, are created by culturing human-tumor derived cells and then injecting these cells into a mouse, which results in subsequent tumor growth. However, lesions that develop in a xenograft mouse often lose certain characteristics of the original human cancers. A number of firms are working on new methodologies to better predict human responses to therapy thereby increasing the probability of success.

Irena Melnikova, Ph.D., is a director at Leerink Swann. Leerink Swann’s MEDACorp is a network of 25,000 physicians, researchers, and healthcare professionals. Web: E-mail: [email protected]

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