The 2015 MPN Challenge
A GRANT PROGRAM SUPPORTED JOINTLY BY THE MPN RESEARCH FOUNDATION AND THE LEUKEMIA & LYMPHOMA SOCIETY
The MPN Research Foundation (MPNRF), with support from The Leukemia & Lymphoma Society (LLS) are proud to announce The 2015 MPN Challenge, a grant program whose objective is to change the trajectory and ultimate prognosis for patients with myeloproliferative neoplasms (MPNs), including MF, PV and ET. This program represents an important partnership between MPNRF and LLS, who share a mission to advance the scientific understanding of MPNs and bring new treatments and the hope for a cure to patients with these rare diseases.
Myeloproliferative neoplasms (MPNs) are a closely related group of hematological malignancies in which the bone marrow cells that produce the body's blood cells develop and function abnormally. The three main myeloproliferative neoplasms are Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (MF or PMF). The MPNs are progressive blood cancers that can strike anyone at any age, and for which there is no known cure. In some patients MPN terminates in conversion to acute leukemia (particularly AML).
In recent years, the MPN community was encouraged by the discovery of the JAK2V617F mutation found in almost all PV patients, and about 50% of ET and MF patients. This first discovery of a genetic mutation that relates to the MPNs ignited a quantum leap in the level of discourse and inquiry into the genetic causes of these diseases. Many resources were directed towards inhibiting the constitutive activity of this mutant JAK2, with the expectation that a successful drug would provide an important new treatment option.
As a consequence of this research, a number of JAK2 inhibitors are currently in clinical trial(s) and one (Jakafi) has now been approved by the FDA for MF and some cases of PV. To date these drugs have demonstrated significant benefits in reducing many constitutional issues (such as enlarged spleen), and with longitudinal studies now underway, may in the future demonstrate a positive impact on disease survival. Additional genetic mutations have been found in some MPN patients (including the exciting discovery of the CALR mutation late in 2013), and are contributing further to our understanding of the genetic complexity of the MPNs.
Perspective of MPN Patients
As patient advocacy organizations, MPNRF and LLS receive many calls and emails from MPN patients, and over many years we recognize common threads. Patients with MF, PV and ET have concerns about symptoms, treatment options, and quality of life, but their most pressing concern is prognosis – will my disease progress, will I get MF, will I convert to AML? Our most harrowing calls are with MF patients, who face the bleakest prognosis and the greatest fears.
The emergence of new treatments for MPN patients is encouraging, but until there is proof that these emerging treatments actually change the course of these diseases, these fears will remain. We at MPNRF and LLS seek to change this future, and we believe a focus on new approaches towards MPN research can change the trajectory of these diseases. We seek the help of independent researchers who can join us in an attempt to achieve that goal.
History of MF/MPN Challenge to Date
In 2011 the MPN Research Foundation and the Leukemia & Lymphoma Society initiated the MF Challenge, a grant program focused on the cause and potential elimination of bone marrow fibrosis in MF patients. We began this program because in spite of the current level of activity in MPN research, there were important questions that remained unanswered, and the most urgent were those associated with MF, the most virulent of the MPNs.
In 2012 and in 2013 the MF Challenge awarded 8 Concept Grants aimed at bringing new ideas, approaches, and investigators to the subject of bone marrow fibrosis. To date, the results are encouraging, and we will continue to seek new approaches in this area until outstanding questions are resolved. However, with increasing numbers of researchers focusing on fibrosis and potential combination therapy, we recognize the need to expand the MF Challenge to other unanswered questions in MPN research. Therefore, in 2014 we renamed our program The MPN Challenge, and while continuing to solicit proposals on fibrosis, we are also looked for applications in other critical areas related to all of the MPNs.
In 2014, the MPN Challenge awarded 10 one-year grants of $100,000 each – a single-year high water mark for this program and for the MPN Research Foundation. As we look forward to our 2015 grant activities, we are continuing to update this program for optimal impact on MPN research. After considerable discussion, we will make the following changes to the 2015 the MPN Challenge:
• Focus areas for proposals (discussed in more detail below) will be changed to reflect new cancer treatment technologies, some as recent as 2014, with the goal of ensuring that MPNs are considered as candidates for these new approaches.
• The term of MPN Challenge grants will be expanded from one year to 2 years, to ensure that critical work can be completed.
The goal of the 2015 MPN Challenge is to stimulate new avenues of research which will strengthen the overall understanding of the cause(s) and potential treatments for all of the MPNs (ET, PV and MF). We are particularly interested in new transformative technologies which are currently being investigated for other cancers. Our goal is to ensure that MPNs are evaluated as candidates for these new approaches. We therefore encourage investigators in other fields whose research may have cross-over application to MPN research.
Why this Approach is Appropriate Now
Based on the response to the MPN Challenge in recent years, MPNRF and LLS are encouraged to believe that ‘paradigm-shifting’ strategies can be identified in many areas of cancer and basic biology research which can be brought to bear in the search for MPN treatments. In 2014 alone, there have been significant advances in immunotherapy, gene editing and other technologies as applied to solid tumor and other cancers. If applied to MPNs, these new strategies, in combination with currently emerging treatments, could truly change the course of the MPNs.
Term of Grant
We have learned in the first years of the MF/MPN Challenge that single-year grants are often not long enough to fully investigate a new avenue of research, resulting in many requests for extended funding. Therefore, beginning in 2015, we will award two-year grants of $100,000 per year. An extensive review of each project after completion of the first year will be aimed at optimizing overall progress through collaboration or resolution of any project obstacles. Towards the completion of the second year, an assessment of overall progress and potential next steps towards translation will be performed jointly by Foundation scientific advisors and grantees.
In November 2014, the MPN Research Foundation convened a group of scientists from both academia and industry to discuss the unmet needs in MPN research, as a guide for future grant programs. This diverse group of current MPN Challenge grantees, academic scientists and representatives of companies currently involved in MPN treatment development held a lively interchange which resulted in the following list of focus areas for the 2015 MPN Challenge:
1. Targeting the Malignant JAK2 Clone
We seek proposals aimed at understanding the importance of the JAK2 allele burden and mechanisms for reducing it in MPN patients, including the following areas:
• studies aimed at determining the significance of JAK2 allele burden as a diagnostic tool.
• research aimed at identifying and testing JAK inhibitors that inhibit the mutant and not the wild-type allele.
• preclinical testing of new agents that demonstrate potential to reduce the JAK2 allele burden.
• basic research and preclinical testing of agents that target the malignant stem cell specifically.
2. Application of ImmunotheraphyApproaches to MPNs.
Basic research to investigate the potential for control of marrow fibrosis and suppression of aberrant MF clones by immunotherapy or immune manipulation. We solicit proposals for immunotherapeutic approaches to the broader spectrum of MPNs that could include, but is not limited to:
• Assessment of the potential role of chimeric antigen receptor therapy (CAR-T) to MPNs.
• Exploration of the role of immune checkpoint regulators in MPNs, e.g., CTLA-4, PD-1, PD-L
• Preclinical testing of antibodies that target the CALR mutated allele.
• Therapy targeted to inflammatory cytokines and/or cytokine receptors and their downstream effectors.
• An understanding of how to combine any of these with evolving standard of care therapies for MPN and in particular, since newly approved agents such as pan-JAK inhibitors have potential to impair immune cell activation and function, how or should they be used with immunomodulatory agents.
Proposals submitted may focus on preclinical or clinical approaches to immunotherapy but proposals that have clear translational potential will be prioritized. Optimal proposals will include a strong collaboration between current immunotherapy experts and MPN specialists.
3. Gene Editing as Applied to MPNs.
We will seek proposals to study whether CRISPR or other gene editing technologies can be applied to MPNs. Our primary objective is to make sure that MPNs are on the table as these technologies are developed. Optimal proposals will include a strong collaboration between current CRISPR experts and MPN specialists.
4. Additional New Mechanisms of Action.
We seek proposals for basic research and preclinical testing of new and innovative mechanisms of action other than those mentioned above (e.g., new targets or pathways), to bring them to the point where other funding options are being directed to these new approaches.
Proposals will be evaluated against the following criteria:
• Relevance to Primary Objective. (see description of Focus Areas above)
• Innovation. We favor proposals designed to allow initial exploration of new ideas with the potential to open new avenues of investigation. MPN Challenge grants are generally NOT intended to support the logical progression of an already established research project, though research that, if successful, ultimately leads to breakthroughs in the diagnosis or treatment of patients with MPNs will be reviewed favorably. Preliminary data are not required to support your scientific rationale.
• Research Strategy and Feasibility. Does the scientific rationale logically support the project and its feasibility? Are the aims, experimental design, methods, and analyses well developed and integrated into the project? Does the PI acknowledge potential problems and pitfalls? Is it a reasonable expectation that the studies will yield meaningful results during the 2 year grant period?
• Collaboration. Proposals that engage interdisciplinary teams and approaches may receive favorable attention, as will proposals made by collaborative teams, either within or across research institutions. Proposal reviewers will also be directed to identify opportunities to repurpose existing resources (e.g., mouse models, other tools) rather than re-invent them; proposals that have already identified such collaborative possibilities will be reviewed favorably.
• Access to Patient Samples. Proposals should demonstrate access to any necessary reagents, including the appropriate number of patient samples, to carry out the proposed experiments. This may be direct access, or access through other sources/collaborations, either which must be clearly demonstrated. It is acceptable to project future patient sample access, but this projection must be realistic. Higher scores will go to those applicants who demonstrate sufficient access to reagents and patient samples to immediately begin their experimentation.
• Commitment to Information Sharing: MPNRF and LLS believe that sharing data is critical for advancing the science as rapidly as possible. While understanding the confidential nature of the research process, it is our expectation that all data will be made public within a year of being generated. We encourage scientific papers, presentations at ASH or comparable venues, smaller meetings, and website publication.
Call for proposals February 2015
Proposal due date April 1, 2015
Scientific Peer Review Committee May 29, 2015 (final review)
Notification of Awards July, 2015
Anticipated funding start date October 1, 2015
The MPN Research Foundation and The Leukemia & Lymphoma Society are committed to moving the results of basic and translational research to MPN patients. To that end, we include in our contracts with the institutions of our awardees Intellectual Property language meant to ensure that no critical results are left without productive follow-up. Should your proposal be selected for an award, we will provide you with this language and ask you to work with your grant office to achieve a timely agreement on these provisions.
Limitation on Contract Negotiation Period
Following award notification, the MPN Research Foundation will interact with each grantee’s institutional grant office to establish a contract for each award. It is our experience that this process can be completed in a 3-month period, especially if the terms of the grant (including Intellectual Property as described above) are reviewed by the grant office prior to submission of the grant proposal. Therefore, in 2015 the MPN Research Foundation reserves the right to cancel a grant if it is not possible to complete contract negotiations by October 1, 2015.
Applicants should prepare a grant application following the format of the application below and email this full proposal to the MPN Research Foundation no later than April 1, 2015. Please title the PDF or Word file as follows: Last Name(space)First Name(space)2015. The proposal should be emailed to the attention of Michelle Woehrle at firstname.lastname@example.org.