ja_mageia

Malignant peripheral nerve sheath tumors (MPNSTs) are among the tumors that can occur in NF1, but these malignancies are particularly challenging to treat and control. One reason for this is that MPNST cells appear to undergo changes that make them reistant to traditional treatments such as chemotherapy. Cuurent Children’s Tumor Foundation Young Investigator Awardee Dr. Thomas de Raedt, a postdoctoral fellow in  the laboratory of Dr. Karen Cichowski at Harvard Medical School, has published a paper this week in leading journal ‘Cancer Cell’ describing his work in mice, showing a new and seemingly highly effective way to treat MPNSTs via a ‘double-hit’ - using two drugs in combination.  Dr. de Raedt and his colleagues combined the drug rapamycin, which targets the cell signaling element mTOR, with the drug IPI-504, which targets another cell signalling element called HSP90.  In the face of this treatment, the mouse MPNSTs underwent dramatic shrinkage. The tumors also underwent what is termed autophagy, where the cells die and collapse under stress so rapidly that they create spaces where the tumors were.  The success of this approach comes from the fact that combining rapamycin and IPI-504 leads to a collapse of cell structures called the endoplasmic reticulum (ER) and mitochondria which together, constitute the energy source or ‘engine’ of the cell.  By shutting down the ER and mitochondria, the cell dies.  We look forward to seeing the next steps of this exciting finding.

Dr. Cichowski and Dr. de Raedt are also members of the Children’s Tumor Foundation Neurofibromatosis Preclinical Consortium.

The 2011 NF Conference kicked off this weekend with some interesting and exciting presentations.  On Saturday, Dr. Filippo Giancotti (MSKCC) provided an update on his novel research first reported in 2010 that described for the first time a role for NF2 merlin protein in the cell's nucleus. Dr. Giancotti has continued to unravel the signaling activities of merlin in the nucleus, and interestingly also showed that in sections of human meningioma tissue,  merlin protein is not present in the nucleus. This would provide support for Dr. Giancotti's unique idea that merlin controls normal cell division and that lack of its nuclear function might be a factor in promoting NF2 tumor growth.  

On Sunday, Dr. Alison Lloyd (University College London) chaired a session on the biology of peripheral nerve development and what we can learn from this and apply to understanding disease and specifically NF1. Dr. Lloyd herself presented some really interesting findings  in mice where Erk signaling was disrupted in peripheral nerves by genetic mutation. The result is that the nerves undergo an inflammatory response, the blood nerve barrier function is lost and in short the nerve looks to all intents and purposes like they have been physically injured. Because Erk signaling is also disrupted in NF1 neurofibromas, this research opens the door to comparing this model of nerve injury to disease progression in NF1 tumors to see what one can teach the other. In the same session Dr. Luis Parada (University of Texas Southwestern) described an ongoing study in which he is screening pairs of drugs from a large compound library on malignant peripheral nerve sheath tumor cells.  The study is beginning to identify potentially novel drug targets for the treatment of these NF1 tumors. Dr. David Largaespada (University of Minnesota) closed out the session with a report o his CTF-funded research focused on better understanding the exact nature of gene mutations that lead to neurofibromas, and how this can help us identify new drug targets. 

On Sunday evening, Dr. Jaishri Blakeley  (Johns Hopkins University) provided an update of her CTF-funded clinical trial of Lapatinib in vestibular schwannomas. This ‘Phase Zero’ trial is focused on giving patients drug prior to vestibular schwannoma surgery so that the excised tumor can be studied to see if the drug reached the target. This type of study provides a rapid preliminary evaluation to determine if a full scale Phase II trial is worthwhile. So far there is not compelling evidence that Lapatinib is effective but the trial is not yet complete so we look forward to seeing the final data.  Dr. Fabio Nunes (Harvard) did a retrospective review of NF2 patients treated with bevacizumab (Avastin) for their vestibular schwannomas, to see if there were also additional effects on meningiomas. While there were modest effects of the drug in some tumors within some patients, this was not strongly compelling suggesting bevacizumab is not likely to be a promising therapeutic for meningioma.  CTF Young Investigator Irma Rangel-Alarcon (UCSF) proposed a function for the protein encoded by the Spred-1 (Legius Syndrome) gene suggesting it has close interactions with the NF1 protein (neurofibromin) in the cell. This study could potentially help unravel why there is overlap in the clinical presentation of NF1 and Legius Syndrome.  

Closing out Sunday evening Amanda Bergner (Johns Hopkins) provided an update of the CTF-funded Schwannomatosis Database which now has 14 US and international sites participating, has enrolled 27 patients and aims to have 200 patients registered by the end of 2011.   

The Children’s Tumor Foundation (CTF) is delighted to announce the funding of five new Drug Discovery Initiative (DDI) Awards totaling $125,000, from applications received for our spring 2011 deadline.   DDI Awards fund studies to test candidate neurofibromatosis (NF) drugs for NF1, NF2 or schwannomatosis, offering $15,000 for in vitro cell-based screens, up to $30,000 for in vivo animal model screens and up to $50,000 to continue outstanding in vivo research projects.  Launched in 2006, it is one of CTF’s most successful programs.

The Spring 2001 DDI Awards are as follows:

Cristina Fernadez-Valle, Ph.D., University of Central Florida - $15,000
In vitro DDI Award to screen a small molecule drug library on NF2 Schwannoma Cells 

Jan Friedman, MD, Ph.D., University of British Columbia - $15,000
In vitro DDI Award to test cytokine inhibitors for the treatment of NF1 Vasculopathy

Xu Wu, Ph.D., Harvard Medical School/ Massachusetts General Hospital - $15,000
In Vitro DDI Award to Test Small Molecule Library of Inhibitors of YAP Nuclear Localization in NF2 Schwannoma, Astrocytoma, Meningioma Cells

David Largaesapada, Ph.D., University of Minnesota - $30,000*
In vivo DDI Award to test of drug combinations for NF1 Plexiform Neurofibroma and MPNST (builds on previous DDI Award of $15,000)

David Wiemer, Ph.D., University of Iowa - $50,000
Advanced DDI Award to optimize Schweinfurthins for NF1 Astrocytoma (builds on previous DDI Award of $30,000)

*Dr. Largaespada’s Award is funded by the Texas Neurofibromatosis Foundation through CTF.

Since its launch in 2006 DDI has funded 44 projects – around 10 per year – of up to $50,000 per Award, totaling a CTF research investment of just over $1 million. DDI studies up to 1 year to complete.  To date, 27 concluded DDI studies have shown promising results and have been successful in securing $4.7M in follow-on funding (to continue building on the CTF-funded research) including government, industry, state and institutional grants. 19 scientific publications have emerged from DDI research, and 19 projects have included collaborations with biotechnology or pharmaceutical companies.  And all of these numbers continue to grow.

DDI forms the backbone of the Children’s Tumor Foundation-funded NF candidate drug pipeline. Through DDI, the NF Preclinical Consortium, and the Clinical Trials Award program the Foundation is currently supporting drug testing bench-to-bedside from cell-based assays in vitro to pilot clinical trials.

The next deadline for DDI Award apps is August 31st and info can be found here.

The Sarcoma Foundation of America is offering grants of $50,000 to support research on the etiology, molecular biology, patho-genesis, diagnosis, and treatment of human sarcomas - which include NF1 MPNSTs. Preference will be given to proposals that focus on novel agents and/or promising molecular targets. including, but are not limited to: c-Met, HDACs, WNT pathway signaling, rank ligand, IGF2; PI3 kinase, Akt, Hedgehog pathway (Ihh, Shh, Dhh), PARP, Notch, and Beta-catenin. Deadline: January 31^st, 2011. Full information: www.curesarcoma.org

For the second year in a row, the Children's Tumor Foundation neurofibromatosis research programs have been recognized and invited for presentation at the Partnering for Cures meeting, which takes place next week in New York. Chief Scientific Officer Dr. Kim Hunter-Schaedle will present in one of the invited "Innovator" slots on the morning of Wednesday December 15th.  Partnering for Cures is organized by FasterCures, an organization formed under the auspices of the Milken Institute to unite non-profit entities focused on medical research  in a forum for information exchange and building collaborations.   This is the second year of the Partnering for Cures meeting, which aims to drive collaboration between non-profit medical research foundations, the pharma and biotech  industry and federal agencies such as the FDA, and investors, in order to accelerate the identification of cures.  Uniquely, at Partnering for Cures, it is the medical research foundations that take center stage, a recognition of  the increasing central role of foundations in advancing research progress to the clinic. As well as two-days of presentations and panels, the meeting provides  an opportunity for one-on-one meetings between potential future collaborators and partners. The CTF Innovator presentation will showcase the Neurofibromatosis Preclinical Consortium (NFPC) in which candidate drugs are assessed in preclinical models of NF1 and NF2 tumor types. NFPC has led to collaborations with companies including Novartis, Genentech and Avila Therapeutics.  NFPC is CTF's biggest investment since 2008 at over $4M, and which we are set to expand for a further two years at $3.5M 2011-2013.