GIST THERAPY RESISTANCE MECHANISMS
YEAR 2 PROGRESS REPORT

Research to identify therapeutic methods that operate in synergy with Gleevec (imatinib) in achieving long-term remission and cure of GIST

Here is the GIST research progress report for year two. In the past year, LRG research funding has enabled progress in identifying novel treatment strategies for GIST. Despite the remarkable clinical responses to KIT and PDGFRA kinase inhibition, GIST clinical progression can occur even in individuals with spectacular initial response to imatinib.   For this reason, LRG is committed to funding research programs to develop synergistic targeted therapies that counteract imatinib-resistance in GIST.  In the past year, research progress was made by studying new treatment methods in GIST surgical specimens, GIST cell lines, and mouse models of GIST.  The urgent aims in all these studies are to identify therapies that function synergistically with imatinib in destroying GIST cells.

Each of the funded scientists performs GIST research that is coordinated with the efforts of the other scientists in this LRG program.  Great pains have been taken to enable collaboration while eliminating redundant research efforts, such that team achievements are emphasized.  This rigorous approach will continue to maximize the LRG research productivity, and – specifically – identify treatment approaches that synergize with imatinib and other KIT kinase inhibitors in enabling a higher cure rate for patients with GIST.

It is hoped that additional research priorities can be supported during the next several years of LRG funding.  In particular, there is urgent need for therapies that operate in synergy with imatinib by increasing GIST cell apoptosis.  The LRG resistance effort would be well-served by encouraging more studies of GIST survival and apoptosis mechanisms.

The imatinib-resistance studies described here are essential to therapeutic progress in GIST.  These studies will likely reveal that combinations of GIST therapies are needed to consolidate initial remissions, forestall the emergence of clinical resistance, and lead to increased cure rates.  At present, the LRG research program funds ten “priority” projects. Each of these projects has substantial, near-term potential for enabling development of novel GIST therapies.  The Year 2 progress for each of these highest-priority projects is summarized below.

Oncogenic signaling mechanisms as novel therapeutic targets: These studies continue to highlight the crucial role of the PI3-K kinase protein in transmitting KIT and PDGFRA oncogenic signals in GIST cells.  Specifically, the LRG research group have shown that a subtype of PI3-K, known as “catalytic alpha” is most relevant in GIST, and future studies will prioritize validations of new drugs that inhibit this particular PI3-K subtype.  The LRG studies have also demonstrated several proteins that bind to KIT in GIST cells: one example is the protein kinase C theta protein, which in the next year will be evaluated as a novel therapeutic target in GIST.

Research Priority Areas

Wildtype GIST:  This project was suspended last year, because there were insufficient numbers of cases identified in the early months of the research program.  Fortunately, substantial progress has been made in the past year, such that KIT/PDGFRA wildtype GISTs, as identified by mutational analyses of paraffin sections, can be used to identify the biologic mechanisms responsible for KIT activation in these cases.  The recent work has identified several kinases, beyond KIT or PDGFRA, that are found at high levels in the wildtype GISTs, and that might serve as additional therapeutic targets.

Primary Resistance:  Some GISTs are caused by KIT or PDGFRA mutations that do not respond well to imatinib.  Research progress in the past year has highlighted that alternate therapies, including sunitinib, sorafenib, and nilotinib can be effective against subsets of these imatinib-resistant primary mutations.  In addition, some KIT kinase inhibitors have greater potency than imatinib against nonmutant KIT, and these inhibitors may be particularly effective against KIT/PDGFRA wildtype GISTs.

Stable disease after imatinib:  Stable disease, i.e. GIST cells that are suppressed but not killed by imatinib, remains a major problem for most people with inoperable GIST.  The recent LRG-funded studies show that a variety of imatinib-resistance mutations can be found at low levels in such stable GIST cells, accounting for partial resistance to therapy.  However, other cells persist in absence of such resistance mutations, and new therapies – particularly those which are highly effective in inducing GIST cell apoptosis – are needed, in conjunction with KIT kinase inhibitor drugs, to destroy those cells.  Future studies will focus on identifying drugs for stable GIST, and developing highly sensitive assays that can detect treatment-resistance mutations in blood samples.

Secondary resistance mechanisms:  Continued progress has been made in identifying drugs that can inhibit secondary imatinib-resistant mutations.  In addition, novel and extremely sensitive assays have been developed to detect low-levels of imatinib (and other KIT kinase inhibitor) resistance mutations in GIST biopsy materials.

Kit Degradation:  These studies have identified small molecule HSP90 inhibitors that are exceptionally effective against the KIT oncoproteins in GIST cells.  Preliminary studies show that greater efficacy, particularly in mouse GIST assays, is obtained with the combination of HSP90 inhibitor and imatinib, compared to using either drug on its own. Future studies will further evaluate these treatment synergies, and will determine mechanisms of HSP90 inhibitor resistance in GIST.

Murine Models:  The laboratories of Drs. Besmer and Rubin have continued to develop mice that develop GIST and are therefore useful in testing new GIST drugs.  Additional progress has included development of mice with imatinib-resistant GISTs, which will provide a system to test drugs of potential benefit for individuals whose GISTs have progressed while receiving imatinib.

Resource Development (imatinib sensitive & resistant):  Exceptional continued progress has been made in developing new immortal GIST cell lines and mouse xenografts, which are indispensable for testing GIST drugs.  The LRG scientists have shown that these resources provide biologically faithful model of GISTs in humans, and as such are highly useful in screening studies to identify new GIST drugs.  Additional cell lines have been developed that permit drug testing against the wide variety of KIT and PDGFRA mutations found in GIST.  These collective resources are, without doubt, one of the great strengths of the LRG research consortium.

Pediatric GIST:  Dr. Antonescu’s research group has continued to shed light on the biological differences between pediatric and adult GISTs. Studies in the past year have shown that the frequency of genetic syndromes, particularly the so-called “Carney’s Triad”, may be underestimated in children with GIST.  A small subset of pediatric GISTs have biologic similarities with adult GISTs, and these tumors can be expected to respond better than others to imatinib.   However, most pediatric GISTs have substantial biologic differences from adult GISTs, including a lack of KIT mutations.  Activated KIT is nonetheless important in these KIT/PDGFRA-wildtype tumors, and lab studies suggest that newer-generation KIT kinase inhibitors, such as nilotinib, might be therapeutically useful in these pediatric wildtype GISTs.

Tissue Banks:  The LRG central repository for frozen and paraffin-embedded GISTs supports the collective research efforts in this program.  These specimens are studied to identify novel oncogenic mechanisms in KIT/PDGFRA-wildtype GISTs, and to identify additional therapeutic targets in GISTs with KIT or PDGFRA mutations.