Given we were discussing bone mets (in the context of prostate ca), this Ariad pre-clinical abstract is of interest:
A novel, bone-targeted mTOR inhibitor that decreases both tumor proliferation and bone breakdown for the treatment of bone cancer.
Chester Metcalf III, Regine Bohacek, Julie Bogus, Heather Knowles, Scott Wardwell, Leonard Rozamus, Kimberly Burns, Lawrence Andrade, Selvaluxmi Pradeepan, Victor Rivera, Hao Tang, Brendan Boyce, Lianping Xing, David Dalgarno, Joseph Snodgrass, Manfred Weigele, John Iuliucci, Tomi K. Sawyer, Tim Clackson. ARIAD Pharmaceuticals, Inc., Cambridge, MA; University of Rochester Medical Center, Rochester, NY.
Cancers of the bone, both those metastatic to bone (bone metastases) and those primary to bone (primary bone cancer), involve complex molecular processes and are extremely difficult to treat. Bone metastases, a frequent consequence of common malignancies such as breast, lung, and prostate cancer, are often associated with severe bone pain and pathological fractures due to increased bone fragility. Primary bone cancers (e.g., osteogenic sarcoma) present treatment challenges, and patients often require limb amputation and/or radiation therapy. In the bone microenvironment, metastasized cancer cells produce activating factors (e.g., PTHrP) that stimulate osteoclast-mediated bone resorption. Bone-derived growth factors (e.g., TGF-? and IGF1) are su bsequently released, promoting cancer-cell proliferation and the amplification of a cycle that produces net osteolytic (bone destructive) consequences. Anti-resorptive agents (e.g., biphosphonates) have been shown to decrease bone lesions as well as tumor burden in vivo, but evidence that such agents have a direct effect on cancer cells at therapeutic concentrations is lacking. The development of bone cancer therapeutic agents that act directly and potently on both processes (bone breakdown and tumor growth) is highly desirable with potential added benefit over existing anti-cancer therapies. The ATM-family kinase, mtor, is a central controller of both cell growth and division, and is activated by external growth factors through the PI3K/Akt signaling pathway. Inhibition of mtor in cells by rapamycin analogs elicits an anti-proliferative and growth-arresting cellular response mimicking the response to nutrient starvation, thus validating mtor as a promising therapeutic target for cancer. Using structure-based drug design, we have synthesized a series of novel bone-targeted rapamycin analogs, exemplified by AP23841, designed to inhibit both tumor growth (mtor inhibition) and bone breakdown (osteoclast inhibition). AP23841 and its analogs have demonstrated nanomolar in vitro inhibition of both human osteoclast activity and of the proliferation of multiple human tumor cell lines. Potent and sustained in vivo anti-resorptive activity has also been observed in a mouse model of PTH-induced hypercalcemia when the compounds are administered either by the oral or intraperitoneal route. Further evaluation of AP23841 and its analogs in animal models of bone metastases and primary bone cancer is underway. The dual-action nature of this class of compounds makes them highly promising candidates for the treatment of both bone metastases and primary bone cancer.
Presenter: Chester Metcalf
Affiliation: ARIAD Pharmaceuticals, Inc., Cambridge , MA . Email: chet.metcalf@ariad.com
Copyright © 2003 American Association for Cancer Research. All rights reserved.
Citation for abstracts scheduled for publication: Proceedings of the AACR, Volume 44, 2nd ed., July 2003.
Citation for abstracts not scheduled for publication: Proceedings of the AACR, Volume 44, 1st ed., March 2003.
Peter |
