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Mouse models of a particular condition such as cancer are often the test subjects for drug therapies long before clinical trials begin. However the question of whether or not mouse results are meaningful in the search for effective drugs is still hotly debated in scientific research, both in universities and industry. Some camps believe that yes, mice with genetically engineered features of a particular diseases or condition are valuable in narrowing down drugs to proceed to human clinical trials; other camps believe that no matter how sophisticated a mouse model of a particular disease is it will never replicate the human condition and therefore using these to test drug treatments is not helpful. Now the Boston Globe reports that Dr. Pier Paolo Pandolfi of Beth Israel Deaconess Medical Center in Boston has leveled the playing field in a research study that gives drugs to humans and mice at the same time. The goal is to better integrate what is learned about a new drug from the mouse with what is learned from the human.  Dr. Pandolfi first used this strategy successfully 15 years ago to develop treatments for then untreatable rare acute promyelocytic leukemia. The value of the ‘co-clinical trial’ approach is that it allows many more drugs to advance through testing at once, particularly combinations of drugs. And by using mice with different genetic mutations, researchers might predict which drugs should work in which patients.

Cheryl Marks, associate director in the division of cancer biology at the National Cancer Institute is quoted as saying “our traditional clinical trial structure . . . is simply not serving us very well.’’ Supporting this new approach is certainly an exciting way of implementing change; and Dr. Pandolfi received a $4.2 million National Cancer Institute grant through economic stimulus (ARRA) funding last year and a further five-year, $3.75 million grant.

Neurofibromatosis research too has the advantage of having a roster of very well developed genetic mouse models replicating all aspects of NF from bone dysplasia, learning disabilities to individual tumor types.  The philosophy of testing drugs in more than one mouse model at a time is one utilized in the Children’s Tumor Foundation NF Preclinical Consortium in which drugs can assessed in up to six tumors of NF1 and NF2 in parallel making sure each drug receives as thorough an assessment as possible. It is an exciting prospect that we might utilize these models as a partner for future clinical trials.

The Children’s Tumor Foundation is currently investing in both traditional and highly novel approaches to developing drug treatments for NF1 plexiform neurofibromas. These are the most common tumor type seen in NF1, and can cause devastating health issues. However researchers now have a reasonable understanding of their biology and are applying this information in developing clinical treatments; and plexiform tumors have been the first NF1 tumor type to advance into a number of ongoing clinical trials.

·         Bruce Korf (University of Alabama at Birmingham) was, in 2009, a recipient of one of our first $125,000 Clinical Trial Awards to assess, in collaboration with Aerang Kim and Brigitte Widemann (National Cancer Institute) the drug Sorafenib in a pediatric plexiform tumor clinical trial.

·         Through the Foundation’s NF Preclinical Consortium, a $4M multi-year initiative to accelerate the most promising candidate drugs to the clinic, the laboratories of Tim Cripe and Nancy Ratner (Cincinnati Children’s Hospital Medical School) are assessing a pipeline of candidate plexiform neurofibroma drugs. The Consortium includes collaborations with Novartis, Genentech, Pfizer and Avila Therapeutics.

·         In a cutting edge approach, Foundation Drug Discovery Initiative Awardee Jonathan Chernoff (Fox Chase Cancer Center) is endeavoring to normalize mast cell signaling in plexiform tumors, as abnormal signaling is believed to promote tumor growth. To do this Dr. Chernoff will develop induced pluripotent stem cells (iPS) - a form of adult stem cells - from mouse skin, and transplant these transplanted into the NF1 mouse bone marrow – the cells should differentiate into normal mast cells which then migrate to the tumor and halt its growth.  

·         Young Investigator Awardee Huarui Zheng (University of Michigan) is also targeting mast cells in mouse models plexiform neurofibromas, this time using targeted drug treatments.  Margaret Wallace (University of Florida) has received two Drug Discovery Initiative Awards in the past year for drug testing on plexiform neurofibromas.  One Award tests PTC Therapeutics VEGF-blocking drug PTC-299 (now in clinical trials at Massachusetts General Hospital for NF2), while the other Award tests indoprofen derivative drugs, which target nonsense mutations in the gene to correct neurofibromin protein production.

·         Outside of Foundation funding, other plexiform neurofibroma clinical trials of note are currently under way. These include: CDMRP NFRP Phase II Clinical Trials Consortium is conducting a trial of Rapamycin in plexiform neurofibroma; Children’s Hospital of Philadelphia has initiated a Phase I (safety) trial of photodynamic therapy for these tumors; and Indiana University has pioneered the use of imatinib mesylate (Gleevec) to treat these tumors.
Look for more NF Bites in the coming days and weeks!