Thalidomide Analogs - Dana-Farber Cancer Institute

Thalidomide alone or in combination with steroids has significant activity in multiple myeloma (MM). However, given its teratogenic potential, analogs have been synthesized, retaining the anti-MM activity without these side effects. We examined the anti-MM activity of two thalidomide analogs, CPS11 and CPS49. Direct cytotoxicity of the drugs on myeloma cell lines and patient myeloma cells was examined using thymidine uptake. Tumor cell apoptosis was evaluated by flow cytometry as well as Western blotting for caspase and PARP cleavage. Cellular signaling events were examined by immunoblotting for phosphorylated proteins. Both drugs inhibit proliferation of several MM cell lines sensitive and resistant to conventional therapies. They decrease secretion of IL-6, IGF, and VEGF by marrow stromal cells. Importantly, they inhibit proliferation of MM cells adherent to stromal cells. These drugs induce caspase-mediated apoptosis in MM cell lines, as well as patient MM cells. They inhibit the PI3K/Akt and JAK/STAT (signal transducers and activators of transcription) pathways in MM cells and are antiangiogenic in matrigel-based assays. CPS11 and CPS49 have potent antimyeloma activity and can overcome protective effects of the tumor microenvironment. They have potent antiangiogenic activity and direct effect on bone marrow stroma. These encouraging preclinical data provide the basis for further evaluation in the clinic.

European Approval for Velcade as 2nd Line Treatment

Ortho Biotech today announced that the European Commission has approved the use of VELCADE® (bortezomib) for Injection as a second-line treatment in patients with multiple myeloma. It is indicated as monotherapy for use in patients who have received at least one prior therapy and who have already undergone or are unsuitable for bone marrow transplantation. With today's announcement, more multiple myeloma patients can hope to receive earlier access to VELCADE® treatment.

Anticanceractivity of IPI-504 in Preclinical Studies

Novel Compound Shown to be a Potent Inhibitor of Hsp90 and Synergistically Cytotoxic with Bortezomib in Models of Multiple Myeloma

Infinity Pharmaceuticals, Inc. announced today positive preclinical data on the company's novel investigational compound IPI-504, a potent inhibitor of Heat Shock Protein 90 (Hsp90). Results demonstrate that IPI-504 significantly reduces tumor burden in several animal models of cancer, including multiple myeloma, breast, lung, and prostate cancer. Furthermore, a key clinical benefit of the compound relative to other Hsp90 inhibitors currently being developed is its proposed administration to patients using a simple water-based formulation. This data was presented during the 96th Annual Meeting of the American Association for Cancer Research (AACR) held in Anaheim, California. The initiation of a Phase I clinical study of IPI-504 is planned for the first half of 2005.

IPI-504 is an innovative and proprietary small molecule compound specifically designed to attack a cancer cell's machinery for maintaining protein homeostasis, the process by which cells continue the orderly formation and destruction of proteins. Hsp90 helps proteins to fold into their correct three-dimensional shape to properly perform their function. Cancer cells are preferentially reliant on Hsp90 activity for proper protein homeostasis because they endure genetic and cellular stresses that alter their normal protein balance. Research shows that inhibition of Hsp90 forces cancer cells to "commit suicide" through a process of programmed cell death or apoptosis.

"IPI-504 demonstrates Infinity's ability to discover and develop proprietary compounds for the treatment of cancer, an area of tremendous unmet medical need," said Julian Adams, Ph.D., Chief Scientific Officer, Infinity. "Protein homeostasis is a very promising and exciting area of focus for cancer research. By focusing on creating a compound that targets this cellular mechanism, we were also able to design IPI-504 to exhibit several advantageous traits -- it binds tightly to Hsp90, shows selective tumor tissue retention at active concentrations for 48 hours, and demonstrates excellent water solubility, enabling a key drug delivery advantage as a simple i.v. infusion."

Study Findings

Infinity's presentation, entitled "Antitumor activity of a novel, water-soluble Hsp90 inhibitor IPI-504 in multiple myeloma" (Abstract #6160) discussed data from in vitro and in vivo studies of Infinity's lead investigational anticancer agent. These studies demonstrate that IPI-504 binds to Hsp90 more tightly than 17-AAG (Ki = 28 nM for IPI-504 vs. 67 nM for 17-AAG) in vitro. In addition, IPI-504 showed potent cellular activity against multiple myeloma, including bortezomib-resistant cells. When used in combination with bortezomib, IPI-504 provided synergistic benefits in its effect on multiple myeloma cells at concentrations significantly lower than their individual IC50s. When examined in vivo, IPI-504 demonstrated a 71% reduction in tumor volume relative to control in the RPMI-8226 human xenograft model of multiple myeloma. It was also found to decrease serum lambda chain concentrations (similar to M protein in the human disease), enabling monitoring of disease burden with a surrogate marker. In an orthotopic model of human myeloma, IPI-504 significantly prolonged the survival of mice relative to the control. This preclinical research was conducted by Infinity researchers in collaboration with investigators at the Dana-Farber Cancer Institute led by Kenneth C. Anderson M.D., Chief, Division of Hematologic Neoplasia.

Diesel Fumes and Myeloma

We examined the relationships between occupational exposures and the risk of multiple myeloma among male construction workers in Sweden. A total of 446 myeloma subjects were identified among 365,424 male workers followed from 1971 to 1999. Occupational exposure was assessed using a semiquantitative job-exposure matrix, based on a survey carried out by the Construction Industry's Organization for Working Environment, Occupational Safety and Health in Sweden. Rate ratios (RRs) in the exposed groups relative to the unexposed groups were estimated by Poisson regression. We found an increased risk (RR = 1.3, 95% CI 1.04-1.71) among construction workers exposed to diesel exhaust. Adjustment for other occupational exposures did not change this estimate (RR = 1.3, 95% CI 1.00-1.77). However, there was no monotonic increase in risk with estimated level of exposure (RR for low = 1.4, moderate = 1.1, high = 1.4). There was no evidence of increased risk associated with the other occupational exposures among these construction workers, including asbestos, asphalt, cement dust, metal dust, mineral wool, organic solvents, stone dust and wood dust. Occupational exposure to diesel exhaust in the Swedish construction industry may present a small risk of multiple myeloma, but lack of an exposure-response trend tempers our ability to draw clear conclusions.

Int J Cancer. 2005 Apr 10;114(3):501

GlycoGenesys initiates trial at Dana-Farber

GlycoGenesys Inc. recently launched a Phase I-II clinical trial of its cancer drug candidate GCS-100LE in multiple myeloma patients.

The primary objective of the Phase I-II dose escalation study is to evaluate the safety of GCS-100LE when given to patients with relapsed or refractory multiple myeloma and to identify the recommended dose for future studies.