First strategic plan to address treatment resistance started

By Norman Scherzer

At an historic breakfast meeting in Boston with Novartis CEO Dan Vasella and Novartis Oncology President David Epstein, Life Raft Group Executive Director Norman Scherzer proposed that Novartis help fund a major research initiative aimed at identifying and overcoming GIST resistance to therapy. In response, Vasella offered to provide the Life Raft Group with $2 million dollars in start up money to support this research. On July 8th the Life Raft Group received the first check in the amount of $1million.

Since then the project has moved forward with deliberate speed. On September 14th, after a series of preliminary planning meetings, the entire LRG Research Team met for the first time by teleconference. Using software to present a PowerPoint overview we reviewed and approved a strategic plan and agreed to a set of basic concepts.

Excellence would replace consensus and collaboration would replace professional competition as philosophical guideposts. Research grants would be driven by a strategic research plan, not by investigator initiated proposals, and the first phase of funding would be directed towards those investigations that offered the best prospects of closing the known information gaps to understanding and overcoming treatment resistance.

Building a different culture:

Rare cancers traditionally have not attracted a great deal of research funding and GIST has not been an exception. Although a great deal of interest has been generated by research breakthroughs in identifying significant pieces of the genetic structure of GIST, particularly since the excitement generated by the incredible success of Gleevec as a front line treatment for this disease, relatively little money outside of clinical trials for new drugs has been focused upon the development of resistance. Certainly the government has allocated almost nothing toward GIST research.

Cancer research is a multi-billion dollar complex industry driven by academic and corporate interests that consume vast amounts of money with markedly mixed results. Although great advances have been made in the treatment of some cancers, particularly those whose treatment is responsive to earlier diagnosis, one could also make the case that too many lives continue to be lost since President Nixon declared war on cancer in 1971.

Until recently, the primary role of patient advocacy groups has been to raise money for cancer research and to appeal to government to do the same. Incredible amounts of energy and creativity have gone into such fundraising and Spring and Fall weekends find legions of patients and concerned friends walking and running with the hope of supporting a search for a cure. Unfortunately this energy and creativity has not been consistently matched on the research side. The presentation of checks to major medical and scientific institutions in the name of research for a given disease has generally not been accompanied by a strategic plan for research nor even a minimal sense of accountability. Thirty-four years is a long time since the declaration of war against cancer and there has to be a better way of fighting it.

In the past few years, a few patient advocacy groups have started to become involved in the process of directing how their research funds should be spent and in creating accountability and oversight for this process. A new culture of research priority focus, coordination and accountability is beginning to emerge. It is that culture that the Life Raft Group has chosen to join and to enhance.

Our objective is clear. We intend to identify the mechanisms of imatinib resistance and the means to overcome them. To leverage our limited resources, our Research Team has drafted a strategic research plan that will enable us to direct grant funds to those research priorities with the greatest prospects of giving us the answers we need and to do so with the greatest possible speed. To complement that strategic process we are creating a supportive grants infrastructure that will hold each researcher accountable for specific results, redirect resources when research dead ends and supplement them when new needs arise. Along the way we believe that we will create a new research paradigm that will help other patient groups.

Ten Priority Projects have been identified:

1. Pediatric GIST: Identify the molecular mechanisms and potential drug targets for Pediatric GIST.

2. Oncogenic signaling mechanisms as novel therapeutic targets: Identify critical parts of the KIT and PDGFRA signaling pathways that will provide synergistic and/or alternate therapeutic targets in GIST.

3. KIT/PDGFRA Wildtype GISTs: Identify the important pathways in GISTs that do not have KIT or PDGFRA mutations using methods, such as cDNA arrays and proteomics, that examine many genes at once.

4. Primary Resistance: Identify resistance mechanisms and evaluate effective therapies for GISTs that are resistant to initial Gleevec therapy. These include specific types of KIT or PDGFRA mutations called “activation loop mutants” and GISTs without mutations in KIT or PDGFRA.

5. Stable disease after imatinib: Identify the mechanisms that cause some tumors to remain stable for long periods, but prevent these tumor cells from undergoing cell death, including development of therapeutic strategies for cells that are not actively dividing (quiescent GIST cells).

6. Secondary resistance mechanisms & clinical evaluation: Evaluate new therapies for GISTs that have developed resistance to Gleevec. These crucial studies will be performed using a variety of methods, such as GIST cell cultures and other cells that have been altered to have KIT or PDGFRA mutations,

7. Kit Degradation: To examine the role of “chaperone” proteins (such as HSP90) that normally protect KIT from being destroyed within the cell, and to evaluate GIST therapies in which these proteins are inhibited, resulting in destruction of KIT.

8. Murine Models: Using mice that have been engineered with KIT mutations, evaluate therapeutic strategies to maximize initial response to Gleevec, as well as the development of resistant mice for the study of therapies for secondary resistance.

9. Resource Development (imatinib sensitive & resistant): Develop additional GIST research resources (tools) including natural GIST cell lines (Gleevec sensitive and resistant) as well as “engineered” cell lines that have been created in the lab with a variety of KIT or PDGFRA mutations.

10. Tissue Banks: Create an adult and a pediatric GIST tissue bank to support GIST research. New and existing tissue from pediatric GISTs, untreated GIST, “stable lesions,” and Gleevec-resistant GIST will be collected, analyzed, and annotated by the various research groups.

Organization:

Group Leaders: Each priority project will have a Group Leader. Each Group Leader will prepare a project plan which allocates implementation responsibility and budgets to individual investigators and which sets specific and measurable milestones. In addition, each group leader will be responsible for overall coordination of the priority group project, including reporting, and for working with other team leaders to share information and, where appropriate, specific data.

Two Phase Structure: We have decided to proceed with a two phase grants process. Phase one will allocate the two million dollars in start-up funding by directing grant funds to those researchers best suited to implement our strategic plan. Phase two will depend upon raising additional funds and will include the more traditional process of investigator driven grants. This directed research phase will permit us to rapidly address those priority areas that have been determined to give us the best options for accomplishing our objectives.

Indirect Costs: Indirect costs will be capped at 10% for all grants greater than $50,000 and will be completely eliminated for all grants up to $50,000. 

Tissue Banks: There will be two GIST tissue banks. An adult tissue bank will be housed at Stanford University under the supervision of Matt van de Rijn and a Pediatric tissue bank will be housed at Memorial Sloan Kettering under the direction of Cristina Antonescu. Each will be responsible for being the point person for the rapid transfer of tissue and data across multiple institutions.

Funding:  Multi-year grants will be permitted but funding will be committed for one year only with non-competitive renewals conditioned upon receipt of satisfactory internal progress reports.

Accelerated funding: In the event that a project completes its yearly project milestone early, the grantee will be permitted to apply for an early start for the next phase. For example, if an applicant achieves its first year project objectives at the end of nine months we would consider awarding the second year of funding three months earlier-conditioned upon the availability of funds.

Supplemental funding: In situations where unexpected costs hinder the successful completion of a priority project, we will consider supplemental funding contingent upon the availability of funds.

Work In Progress: We are engaged in a battle against time and we are trying to create a research process that will balance the urgent survival needs of patients against the time needs of scientists to find answers to hard questions. The patient and thoughtful guidance provided by Dr. Jonathan Fletcher has been the key to developing a sophisticated plan of action. We are very much a work in progress. The survival of GIST patients demands that we succeed and it is to that end that we are committed.