This morning began bright and early with a committee meeting of the Children’s Foundation Clinical Care Advisory Board which, amongst other activities, oversees our NF Clinic Network and is this summer charged to take forward our patient Registry and BioBank for an anticipated launch in late 2010. At the Conference itself, Jeffrey Settleman (Harvard Medical School) gave a keynote talk on tumor resistance mechanisms, and proposed his model that tumors can evolve and a sub population of cancer cells may become resistant to drug therapy and represent those cells that will drive future tumor recurrence. Following this was an exciting session focused on understanding and targeting NF1 signaling. Karen Cichowski (Harvard Medical School) is testing candidate drugs for malignant peripheral nerve sheath tumor (MPNSTs) in genetic mouse models that develop this tumor. She presented some exciting data illustrating that a combination drug therapy of Rapamycin plus agents that cause endoplasmic reticulum stress will in combination induce tumor cells to undergo autophagy (‘self –eating’). As both drugs have already been used in (non-NF) patients, they may be worth pursuing as MPNST therapies in humans. Kevin Shannon (UCSF) reviewed his recent studies using leukemia ‘factory mouse’ models for rapid screening of drugs and drug combinations. Dr. Shannon is using this model to test drugs through the CTF NF Preclinical Consortium including inhibitors of PI3K, mTOR and MEK. Luis Parada rounded out this session with a presentation of his hypothesis from genetic mouse models that plexiform neurofibromas become ‘defined’ early in life during a particular period of development, while Schwann cells are precursors or immature. This intriguing but very preliminary and early stage theory points toward the suggestion that in an individual with NF1, future plexiform neurofibromas become pre-determined at the cellular level early in life.
Today’s agenda began and ended with a focus on NF2 molecular signaling and the challenges that lie ahead to fully understand it. The morning opened with presentations from Andi McClatchey (Harvard Medical School), Helen Morrison (Institute for Aging) and Filippo Giancotti on the signaling mechanisms of merlin in the cell cytoplasm and nucleus (an important topic that was covered by the same individuals at the Las Vegas meeting last month). However the NF2 highlight of the day was a late-afternoon panel discussion ‘New Frontiers in NF2 Research’ chaired by Dr. Jon Chernoff (Fox Chase Cancer Center) and featuring Dr. McClatchey, Giovanni and Giancotti as well as Dr. Gareth Evans (Manchester), Dr. Vijaya Ramesh (Harvard) and Dr. Oliver Hanemann (Plymouth). Panel members each presented a slide on something they felt was important for the NF2 community at large to pay attention to in order to advance our understanding of NF2 biology and ultimately find effective drug therapies. These included the need to better understand merlin protein biochemistry and its full variety of binding interactions whether these are in the nucleus or in the cytoplasm; a call to spend more time testing drugs on human tumor cells; the need to fully evaluate all of the mutations in the NF2 gene and their consequences.
This evening we are headed out for a harbor cruise on the paddlewheel boat ‘Black Eyed Susan’ for an evening of ‘diagnostic dilemmas’ where clinicians will share with each other difficult cases for discussion and brainstorming. A report to follow tomorrow!
