New Drug to Treat Multiple Myeloma Bone Disease

Ann Arbor, Mich. Sept. 24, 2007 - Velcura Therapeutics, Inc., a biotechnology company developing therapies for bone disease, met with the U.S. Food and Drug Administration (FDA) Sept. 20 to clarify details for the early clinical development of VEL-0230, a drug developed to treat bone disease. The focus of the Pre-Investigational New Drug Application (IND) meeting was to obtain feedback from the FDA’s Division of Oncology Drug Products about Velcura’s completed preclinical studies, as well as Velcura’s near-term clinical development plans for VEL-0230. VEL-0230 is a new chemical entity that has dual-acting properties that both stimulates bone formation and inhibits loss. The company, a 2007 Michigan 50 Companies to Watch award winner, plans to initiate clinical trials in 2008 for the use of this drug as a treatment for Multiple Myeloma, a blood cancer associated with profound bone loss.

VEL-0230 is being studied preclinically for the treatment of diseases involving bone mineral disorders such as bone loss related to multiple myeloma, osteoporosis, bone metastases, and rheumatoid arthritis. Given VEL-0230’s promotion of bone formation, inhibition of bone loss and reduction of calcium levels, Velcura has chosen Myeloma as its lead indication, as the bone fragility, bone pain, high calcium levels and eventual kidney involvement present serious medical and quality of life issues to affected patients.

Source: www.velcura.com

Attention Relapsed/Refractory Myeloma Patients

If you are a myeloma patient with Relapsed (your disease has progressed) and/or Refractory (you have not responded to initial therapy or have relapsed within six months of initial therapy) disease, and your disease has progressed despite treatment with new therapies like Revlimid and Velcade, there are clinical trials with new treatment options available to you.

By calling 800-506-9044, a trained clinical trials specialist will help you to complete a personalized profile to find trials that are right for you. The service is free and all submitted information is kept strictly confidential. Alternatively, log on to www.MyelomaTrials.org, and complete the profile yourself.

It is important for you to know that you do have options even if you are no longer responding to the latest therapies. And, the more people who participate in clinical trials, the faster critical research questions can be answered that will lead to better treatment options for all patients.

Signaling protein identified in Multiple Myeloma

Emory Researchers Identify Signaling Protein That May Result in New Therapeutic Target for Multiple Myeloma

Atlanta -- Researchers at Emory University's Winship Cancer Institute are the first to discover a mechanism that plays a critical role in the multiple myeloma cell cycle and survival. Their research may result in identification of a new therapeutic target for treating multiple myeloma.

The results of the study appear in the September issue of Cancer Cell. Jing Chen, PhD, an assistant professor of hematology and oncology at Emory Winship and a Georgia Cancer Coalition Distinguished Cancer Scholar, is senior author on the paper. Sumin Kang, PhD, a postdoctoral fellow at Emory Winship, is the paper's first author. In addition, Cancer Cell has included a preview of this paper in the same issue, highlighting the impact this study will have on multiple myeloma research.

Multiple Myeloma is among the most common hematologic malignancies in patients over 65. Approximately 15 percent of multiple myeloma patients harbor a genetic abnormality called "t(4;14) chromosomal translocation" that causes over-expression of a tyrosine kinase called fibroblast growth factor receptor 3 (FGFR3). Tyrosine kinases are molecules that act as biological switches inside cells, regulating processes including cell division and growth. Abnormal kinases have been identified as a driving force in many forms of cancer.

"We are interested in how FGFR3 mediates transforming signals," says Dr. Chen. "We wanted to know which protein factors in cells are activated by FGFR3 and then transform normal cells to highly malignant cells. We identified Ribosomal S6 kinase 2 (RSK2), which is a protein factor that mediates signaling in cells as critical in downstream signaling of FGFR3 in myeloma cells."

Dr. Chen and his colleagues are the first to discover a mechanism to "turn-on" RSK2 by FGFR3. FGFR3 impacts downstream proteins through phosphorylation at special "tyrosine" sites. "We found that FGFR3 directly phosphorylates RSK2, which is a critical step in the process to activate (turn-on) RSK2," says Dr. Chen.

The researchers observed that elimination of RSK2 proteins or shutting down RSK2 activity blocks FGFR3 transformation signaling in myeloma cells. This means FGFR3 requires RSK2 to transform normal cells. "This is a beautiful model," says Dr. Chen. "We are able to mark the connection between the oncogenic FGFR3 and its downstream protein kinase RSK2, which plays a critical role in regulation of cell cycle and survival. These findings extend our understanding of pathogenesis of multiple myeloma in a signaling basis."

Collaborators on the project include Roberto Polakiewicz, PhD, and Ting-Lei Gu, PhD, both of Cell Signaling Technologies (CST), developers of the "PhosphoScan" technology, which enables investigators to identify hundreds to thousands of phosphorylated sequences and observe the global state of protein tyrosine phosphorylation in cells and tissues. "Using this technology," says Dr. Chen, "we identified RSK2 as a critical downstream signaling protein effector of FGFR3 in myeloma cells." Other authors include researchers from the University of California at San Francisco, Harvard Medical School, Mayo Clinic and Novartis Pharma AG.

Dr. Chen and his colleagues also tested a drug called fmk that was designed by co-author Jack Taunton, PhD, at UCSF to specifically target RSK2 in treatment of human malignant myeloma cells from laboratory culture or primary samples from multiple myeloma patients, and saw that fmk effectively kills t(4;14) myeloma cells with abnormal over-expression of FGFR3. "This study shows the potential utility of drugs that block the downstream effectors of mutant tyrosine kinases, and that these drugs are opening more doors to treating hematologic malignancies and cancers," explains Dr. Chen.

In addition to the t(4;14) in multiple myeloma that is caused by abnormal over-expression of FGFR3, abnormality of FGFR3 has also been identified in human bladder and cervical cancers. The findings suggest, the authors write, that targeting RSK2 with RSK inhibitors such as fmk may be effective in treating t(4;14) multiple myeloma, as well as other diseases and cancers where mutant FGFR3 is the culprit.

Source: http://cancer.emory.edu/

Inhibition of Akt inhibits Myeloma cells

Inhibition of Akt induces significant downregulation of survivin and cytotoxicity in human multiple myeloma cells.

Hideshima T, Catley L, Raje N, Chauhan D, Podar K, Mitsiades C, Tai YT, Vallet S, Kiziltepe T, Ocio E, Ikeda H, Okawa Y, Hideshima H, Munshi NC, Yasui H, Richardson PG, Anderson KC.

Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.

Akt mediates growth and drug resistance in multiple myeloma (MM) cells in the bone marrow (BM) microenvironment. We have shown that a novel Akt inhibitor Perifosine induces significant cytotoxicity in MM cells in the BM milieu. This study further delineated molecular mechanisms whereby Perifosine triggered cytotoxicity in MM cells. Neither the intensity of Jun NH(2)-terminal kinase phosphorylation nor caspase/poly (ADP-ribose) polymerase cleavage correlated with Perifosine-induced cytotoxicity in MM.1S, INA6, OPM1 and OPM2 MM cells. However, survivin, which regulates caspase-3 activity, was markedly downregulated by Perifosine treatment, without changes in other anti-apoptotic proteins. Downregulation of survivin by siRNA significantly inhibited OPM1 MM cell growth, confirming that survivin mediates MM cell survival. Perifosine significantly downregulated both function and protein expression of beta-catenin. Co-culture with BM stromal cells (BMSCs) upregulated both beta-catenin and survivin expression in MM cells, which was blocked by Perifosine. Importantly, Perifosine treatment also downregulated survivin expression in human MM cells grown in vivo in a severe combined immunodeficient mouse xenograft model. Finally, Perifosine inhibited bortezomib-induced upregulation of survivin, associated with enhanced cytotoxicity of combined bortezomib and Perifosine treatment. These preclinical studies provide the framework for clinical trials of bortezomib with Perifosine to improve patient outcome in MM.

PMID: 17760810 [PubMed - in process]