A Novel, Bone-targeted mTOR Inhibitor that Decreases Both Tumor Proliferation and Bone Breakdown for the Treatment of Bone Cancer (Abstract 717)
A new bone-targeted rapamycin analog, AP23841, is designed to inhibit primary bone cancer tumor growth and halt the growth of bone metastases, according to researchers at ARIAD Pharmaceuticals, Inc., Massachusetts. Rapamycin is an immunosuppressant indicated to prevent organ rejection.
Using structure-based design, scientists in this study produced a series of analogs, exemplified by AP23841, to inhibit the mTOR protein as well as bone breakdown. The ATM-family kinase, mTOR, is a central controller of both cell growth and division, and is activated by external growth factors and nutrients. Inhibition of mTOR by analogs elicits a growth-repressing cellular response, thus validating mTOR as a promising therapeutic target.
"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," said lead investigator Chester A. Metcalf III, Ph.D., a principal scientist of chemistry at ARIAD Pharmaceuticals, Inc.
AP23841 and its analogs have demonstrated in vitro (outside the body) inhibition of both processes. In addition, when the compounds are administered orally or through the peritoneal lining within the abdominal cavity, potent and sustained in vivo (inside the body) anti-resorptive activity (to prevent from breaking down) has been observed, which has been shown to decrease bone lesions. Further evaluation of AP23841 and its analogs in animal models of bone metastases and primary bone cancer is underway.
Efficacy of Radioimmunotherapy with Radiolabeled HerceptinTM in Combination with Gemcitabine in the Treatment of Intraperitoneal Disease (Abstract 5787)
Treatment regimens combining chemotherapeutics and radioimmunotherapy may have tremendous potential in the management and treatment of cancer patients, according to a study presented by researchers from the National Cancer Institute. HER2, a member of the epidermal growth factor receptor family, is a promising target for radioimmunotherapy, (RIT) a therapy that uses antibodies as vehicles to direct radiation to tumor cells.
In this study, researchers examined the therapeutic efficacy of radiolabeled HerceptinTM (labeled with a radioactive atom or substance) for the treatment of metastatic disease using two intraperitoneal tumor animal models: LS-174 T, a human colon cancer cell line, and SHAW, a human pancreatic cancer cell line. Studies were initiated in which a single dose (1 mg) of gemcitabine was administered to athymic mice (lacking a thymus) with colon cancer xenografts (cross-species transplants) 24 to 30 hours prior to receiving a single dose of Herceptin. This follows previous research that showed radiolabeled Herceptin has exhibited encouraging therapeutic efficacy in tumor targeting and improved survival rates of athymic mice, and that gemcitabine has been administered successfully as a radiosensitizing agent in conjunction with radiotherapy.
The survival rates for 50 percent of the colon cancer mice were: Herceptin with gemcitabine, 70 days; Herceptin, 45 days; gemcitabine only, 32 days; and saline-treated, 18 days. Similar studies that treated mice with pancreatic cancer xenografts with radiolabeled Herceptin and gemcitabine were not as successful. The use of gemcitabine increased the survival of animals from 45 to 70 days, suggesting a clinical enhancement of treatment. Other studies are currently assessing the efficacy of radiolabeled Herceptin, and multiple, weekly injections of gemcitabine following RIT in the colon cancer model.
"We believe that the use of radiolabeled monoclonal antibodies, like Herceptin, are a viable option for the treatment and management of cancer patients, and treatment regimens including chemotherapeutics hold great potential," according to Diane Milenic of the National Cancer Institute, and lead investigator of the study.
MAC-321: A Novel Taxane with Greater Efficacy than Paclitaxel and Docetaxel In Vitro and In Vivo (Abstract 5779)
A novel taxane inhibits the growth of paclitaxel and docetaxel-resistant tumor cell lines, according to data presented by scientists at Wyeth Research, Pearl River, NY. Both paclitaxel and docetaxel are widely used for the treatment of lung, breast and ovarian cancers, but many tumor types eventually become resistant to the drugs. In this study, researchers examined a novel compound in the same class, MAC-321, which inhibits the growth of paclitaxel and docetaxel-resistant tumor cell lines grown in vitro and in vivo.
Similar to paclitaxel and docetaxel, this compound enhances the rate of tubulin polymerization in vitro and causes the bundling of microtubules in cells. Tubulin polymerization is the promotion of assembly and prevention of disassembly of cell microtubules, structural elements that assemble and divide throughout cell life. With the use of the compound, the normal reorganization of the microtubule network is repressed, halting cell division and other vital cell functions.
Researchers discovered that a single 70 mg/kg IV dose of MAC-321 eliminated detection of tumors that were partially responsive to a single dose of paclitaxel. Additionally, the compound either partially or completely inhibited tumor growth in three tumor models resistant to paclitaxel. Lastly, unlike paclitaxel or docetaxel, MAC-321 was effective when administered orally. The compound is currently under clinical evaluation.
"MAC-321 is a novel agent that Wyeth is jointly developing with Taxolog, Inc. MAC-321 has greater pharmacological efficacy in vitro and in vivo than the currently approved taxanes," said Dr. Deepak Sampath, of Wyeth Research in New York. "Our findings suggest that the compound may have broad therapeutic value."
Founded in 1907, the American Association for Cancer Research (AACR) is a professional society of more than 20,000 laboratory and clinical scientists engaged in cancer research in the United States and more than 60 other countries. AACR's mission is to accelerate the prevention and cure of cancer through research, education, communication and advocacy. Its principal activities include the publication of five major peer-reviewed scientific journals (Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention). AACR's annual meeting attracts more than 12,000 participants who share new and significant discoveries in the cancer field, and the AACR's specialty meetings throughout the year focus on all the important areas of basic, translational and clinical cancer research.
Contact: Warren Froelich/AACR
froelich@aacr.org
215/440-9300
Aimee Frank/Spectrum Science
amf@spectrumscience.com
202/955-6222
In Washington, DC: (7/11-7/14)
Washington Convention Center
202/249-4060