June 15, 2010 (Vol. 30, No. 12)
MBC Pharma’s Technology Allows Anticancer Drugs to Penetrate Down to the Bone
In 1996, MBC Pharma was incorporated as MBC Research. Its founders quietly pursued the development of a bisphosphonate-based platform discovered by the late Marat Karpeisky, Ph.D., D.Sc., at the Engelhardt Institute of Molecular Biology at the Russian Academy of Sciences in Moscow. After moving to Boulder, CO in 1993, Dr. Karpeisky teamed up with Hal Dixon, Ph.D., at the University of Cambridge, U.K., and Lee Sturgeon, a businessman in Boulder, CO, to start the company. The letters in the company’s name stand for Moscow, Boulder, and Cambridge. In 2005, Alexander Karpeisky, Ph.D., Marat’s son, became vp of research and is now president and CSO.
MBC’s technology platform improves the oral bioavailability of bisphosphonates and exploits their bone-seeking properties to deliver pharmacological agents to the bone and surrounding tissues. Along with colleagues at the Mayo Clinic, Dr. Karpeisky published what the firm says was the first proof-of-concept study in the February 2002 issue of Breast Cancer Research.
Physicians have prescribed bisphosphonates for more than 30 years to treat osteoporosis and other metabolic bone disorders. The core compounds continue to evolve and are in their third generation. Some of the latest products such as Zometa® (Novartis) require just a once-a-year injection. However, “most of the work we’re doing is built around earlier generations of bisphosphonates, which are off patent, yet perfectly suited to bone targeting,” says Dr. Zinnen. The company’s primary focus is on oncology rather than osteoporosis.
In October 2009, the U.S. Patent and Trademark Office issued MBC Pharma a patent that covers methods for making and using bone-targeting anticancer conjugates. The compounds are constructed by combining a range of approved bisphosphonates with almost any approved anticancer drug or compound. “This gives us a healthy IP footprint,” Dr. Zinnen adds.
The patent comes at a fortuitous time when other researchers are discovering that the bone microenvironment plays a surprisingly complicated role in tumor metastases beyond what was previously recognized. A surge of research reports in the past five years show that the bone marrow microenvironment provides a sanctuary for tumor cells that metastasize from primary tumors, including prostate, breast, lung, and leukemia.
Within niches of the bone marrow microenvironment, subpopulations of cancer cells evade chemotherapy and become drug-resistant. The bone marrow refugees also may travel via the bloodstream to distant organs, where they seed new metastatic sites and attract circulating tumor cells. When in the bone marrow, tumor cells profoundly upset bone metabolism and cause bone destruction. “There’s lots of excitement about what targets to go after to shut down the bone involvement in tumor growth,” says Dr. Karpeisky.
The emerging scientific evidence is driving a paradigm shift that views the bone, not only as a sanctuary for metastatic cancer cells, but also the source of tumor supporting cells that aid the growth of both bone and nonbone metastases.
“Our patent-protected position is on the cutting edge of this paradigm shift in oncology drug development,” remarks Dr. Zinnen. “Almost any conventional anticancer compound can be distributed to bone in pharmacologically relevant concentrations with our approach,” adds Dr. Karpeisky.
The first generation of the company’s anticancer bisphosphonate conjugates are based on phosphate linkages between anti-neoplastic nucleotide analogs and simple bisphosphonates that bind bone and release both drugs. The conjugates kill cancer cells in the bone as well as osteoclasts (cells that break down bone) to prevent bone loss. The company’s lead compound, MBC-11, uses the cytotoxic analog AraC to kill rapidly growing cancer cells. AraC, also known as cytarabine, is a chemotherapy drug used to treat different forms of leukemia.
Researchers at MBC Pharma are testing MBC-11 in an animal model for multiple myeloma, and preclinical studies show that MBC-11 works well in breast and prostate models, too. “That surprised us,” says Dr. Zinnen, “because AraC is typically used to treat hematological cancers like leukemia or multiple myeloma.” By conjugating AraC to a bisphosphonate, the cytotoxic agent acquires novel properties that allow it to attack cancer cells of epithelial solid tumor origin.
Boosting Absorption with B6
A related technology platform at MBC Pharma links vitamin B6 (pyridoxal phosphate) to bisphosphonates to improve their bioavailability. Most oral bisphosphonates taken for osteoporosis readily enter bone cells, but only about 1% of the dose is absorbed from the intestines. Adding B6 greatly enhances absorption, since almost all cells in the body have receptors for the vitamin that transports the bisphosphonate across the intestinal membrane. Once the conjugate is in circulation, the enzymes that metabolize vitamin B6 release the bisphosphonate portion for distribution to the bone. At this time, however, the development of B6 platform has been placed on hold in order to concentrate on developing conjugates for the oncology platform.