Sarcoma and GIST Cancer TRDG: Meetings and Minutes

Agenda:

The current status of translational research efforts at FCCC and Temple in the particular disease site including the status of Investigator-initiated trials and opportunities based on science and feasibility.
Opportunities for collaboration based on existing ongoing activities or through knowledge of developments in the field.
To exchange information regarding funding opportunities.
To consider multidisciplinary programmatic efforts that may be supported by P01s or SPOREs.
To discuss progress that is being made through more focused presentations by specific investigators or subgroups.
To take full advantage of institutional capabilities and resources in terms of genomics, tissues, CTO, and to integrate across programmatic efforts, basic or clinical research activities and tumor boards.
To bring in additional investigators including lab members/trainees involved in translational research.

The TRDGs strive to recognize and develop opportunities for collaborative translational research directions by providing a focused forum for exchange of information among a diverse group of stake-holders interested in a particular disease site. Before each meeting, depending on the particular expertise, participants are asked to review/be prepared to discuss the current disease site early phase investigational protocols at FCCC, the potential opportunities in industry with available targeted agents, potential collaborations with other institutions that have activated protocols with novel agents, specific molecular targets or signaling pathways for the disease site at FCCC, resistance mechanisms, potential biomarkers that can be incorporated into protocols, and the major open questions for the disease site or other more general questions in the field that could be addressed for the disease site.

10-6-16

Dr. Jimson D’Souza spoke about “Advances in Translational GIST Cancer Research”. He described PDX models and novel kinase targets. He has implanted 18 cases over the last couple of years. Several are growing tumors and he described gene changes in different models as well as emerging information on resistance to therapy. A question was raised as to whether it is known if more heavily treated patients are easier to make PDX models from. Dr. D’Souza mentioned that some of the models have been serially passaged in mice and he described collaborations that will assist in molecular characterization of models. There was additional discussion about different patterns of mutations in GIST and drug targeting approaches.
5-11-16

Dr. El-Deiry spoke about R21 RFA in clinical and translational studies. Dr. Martin Belinsky spoke about “NF1 deficiency in GIST”. He started with whole exome sequencing (WES) of a case supported by Sarcoma Foundation of America. He described the ‘omic’ efforts in the GIST group... Expand
Kinome profiling project with 28 samples with major mutation groups Kit and PDGFR-alpha, and WT that have succinate dehydrogenase mutation. Dr. Belinski recently reported on some of these findings (https://www.ncbi.nlm.nih.gov/pubmed/23730622). Dr. Belinsky described whole transcriptomic sequencing in GIST and whole exome sequencing. He described the case of a 54 year old woman with high risk (location, size and number of mitoses) sporadic small intestinal GIST. The patient had had multiple resections over 6 years from 2008. The tumor was WT KIT, PDGFRA, BRAF, KRAS (hot spot exons). Not typical WT GIST as SDH was WT; demonstrated SDHB staining as well as Kit staining. WT GIST is usually in the stomach (not SI). He looked at chromosome gains and losses and did germ-line and tumor sequencing. Candidates were prioritized by deleterious types whether missense, frameshift (fs), or splice site; targeted protein expression. He found NF1 and MAX mutations that were homozygous; both were frameshift. A paper was published in BMC Cancer (https://www.ncbi.nlm.nih.gov/pubmed/26555092). This was the first somatic NF1 loss in GIST and novel with regard to MAX. IHC was peformed looking for MAX and found other examples with MAX loss. NF1 is negative regulator of Ras signaling. Dr. Belinsky described features of Neurofibromatosis type I (NF1) in humans. NF1 which is an autosomal dominant disorder has 45x increased risk of GIST. He spoke about various types of NF1 associated cancers (MPNST, rhabdo, JMML, GIST, pheo, carcinoid, breast ca, neuroblastoma, optic pathway gliomas). NF1 loss has been seen sporadically. Actual mutations in the case report was not seen in the database. There is no known GIST in NF1 mouse. Dr. Belinsky further spoke about molecular diagnostic implications and is looking at whether there is a larger role for NF1 in sporadic GIST. He described ongoing collaborations and future directions based on NF1/MAX findings. He spoke about the potential for binimetinib in GIST (http://meetinglibrary.asco.org/content/150696-156). Collapse
3-9-16

Dr. Meg von Mehren spoke about PARP inhibitors in sarcoma. Imatinib resistance lab work led to insights as far as c-KIT mutations and patterns with different other drugs. ... Expand
Akt is activated in imatinib resistant GIST. MK-2206 is an allosteric Akt inhibitor currently in clinical testing. MK-2206 has some activity versus imatinib resistant cells and synergizes with imatinib. The results were recently published (https://www.ncbi.nlm.nih.gov/pubmed/27370604). Using spheroid assay to demonstrate sensitivity. Showed results of xenograft studies and effects of the combination. Saw less p-Akt in the xenografts. She is evaluating different Akt inhibitors with potential for translation as a phase Ib trial. Dr. vonMehren described some available philanthropic funds for Ewing’s Sarcoma Research. Ewing’s is the 2nd most common cancer in bone; seen most frequently in 2nd decade of life. Affects the long bones and 25% have metastatic disease. The 5-year survival after relapse is 13%. EWS1-FLI1 is most common driver and there are fusions with other Ets factors. There is a link to PARP. Ets transcription factors interact with PARP1. There is data with Olaparib in Ewing’s lines. She discussed results from Garnett et al Nature 2012. EWS-FLI induces PARP1. PARP1 can stimulate EWS-FLI and so there may be a role for a PARP inhibitor. Preclinical studies in xenografts have not shown single agent olaparib activity, and there have been no responses in phase II study. In cell lines, combination of chemo such as temozolomide or irinotecan with PARP inhibition had activity. She mentioned a 2015 AACR abstract on JQ1 inhibition of EWS-FLI and there was discussion about use of other PARP inhibitors. There was discussion of work by Dr. Movva with Caris and looking at Ewing’s tumors. There is a need for a TMA. There was apparently a leiomyosarcoma microarray generated at FCCC years ago per Dr. Lori Rink. There was mention of CDK4 and MDM2 in a subset of Ewing’s sarcoma. There will be a trial of CDK4 inhibitor with mTOR inhibitor at FCCC in liposarcoma. There was discussion about FAK and FAK inhibitors and a question about exosomal materials for sarcoma. Collapse
10-29-15

Dr. Sujana Movva currently has 3 investigator-initiated trials including a Takeda mTOR1/2 inhibitor for sarcoma with PTEN loss (40%), a collaboration with Dana Farber on CDK4 inhibit plus mTOR in liposarcoma (80% overexpress CDK4), and an EPCRS grant to look at biomarkers of sensitivity to doxorubicin in soft tissue sarcomas... Expand
There was mention of Chk2 inhibitors (Dr. Finnberg) and PARP inhibitors (Dr. Tulin) as areas of interest. There was mention of PDX models of GIST and a question if is there a national effort for PDX models in sarcoma. Dr. Edna Cukierman spoke about fibrosis-like neoplastic reactions; mechanisms and biomarkers. The fibrosis is a railroad for intravasation. Cancers are wounds that never heal. The stroma can influence angiogenesis, immune responses, local connective tissue participation in epithelial cancers. Stromagenesis is a process known as desmoplasia in epithelial cancers. There are no markers for activated connective tissue with and without mutation in sarcoma. It would be useful to help understand sarcoma. Pancreatic cancer has a major component of stroma. Dr. Cukierman has access to fresh clinical samples through an IRB protocol. There was discussion about how different sarcoma types interact with their stroma. Myxoid, leiomyosarcoma, liposarcoma. It was suggested to consider asking Dr. Pachefsky to speak about this at a TRDG meeting. Stroma in culture makes its own ECM. Dr. Cukierman isolates tissue derived fibroblasts and creates a 3D cultures and does experiments to explore field effect in cancer e.g. in pancreatic cancer. There was a question about how much stroma is in sarcoma and how does it vary in different types. Dr. Cukierman mentioned interest in PDX models. There was discussion about organoids, microfluidics, bioreactors and interest in reversing or reprogramming stroma, FAK and integrins as targets for therapy, issues with specificity of agents and the availability of FAK inhibitors. There was discussion about collecting preliminary data to move in direction of IITs in sarcoma with such targets. Dr. Cukierman is interested in looking at effects of therapy on the stroma and has done microarrays in various tumor types with candidates that may confer metastatic escape. How is the stroma participating in the drug resistance. Collapse
4-28-15

Dr. Lori Rink spoke about imatinib resistance in GIST with primary and secondary resistance. There is an effort to establish PDX models, efforts to study role of KRAB-ZNFs in rapid response to imatinib, and MK-2206 Akt inhibitor studies. 4 PDX models have been established since March. A liver metastasis from a non-responder was established. All from surgical specimens. All are in progress as far as in vivo growth. They have in the past tried to grow cell lines but it is difficult due to slow growth of the tumors... Expand
There was discussion with Dr. Farma regarding trying to get more samples. Several were obtained through Dr. Esnaola. Looking for imatinib naïve or progressive resistant tumors. She spoke about expression profiling to predict response to imatinib. RTOG S-0132 neoadj imatibin to surgery or off study if PD after surgery. All pts ewre imatinib naïve. 18 institutions, 63 pts, 52 analyzable. 30 primary 20 metastatic GIST. 38 genes up in non-resp gp. 20 had CRAB-ZNF. Family of transciptional repressors. CRAB-ZNFs recruit TRIM28. ZNFs amplify and deleted in CRC as well. Did synthetic lethal screen for imatinib sensitizers. A bunch of ZNFs came out of the screen and could also sensitize to sunitinib, but few to doxorubicin and none sensitized to ifosfamide. Now interested in the targets of the ZNFs. Periostin, TGF-beta3, NEDD9 emerged; went back to RTOG trial samples and made correlations with expression. Started looking at circulating levels of TGF-beta1-3 and periostin and made corelations with imatinib response. Non-resp GISTs to imatinib had much higher levels of periostin and TGF-beta2. Dr. Sujana Movva spoke about clinical projects. She mentioned collaboration with Caris on 2000 sarcoma cases including many subtypes. Looked at various markers—reported at ASCO in 2014. Found fairly infrequent mutations including p53, PTEN, PIK3CA. TOPO2A overexpressed in 50%, PTEN loss in 80%, some EGFR overexpression, and PD-L1 expressed in 100% liposarcomas. There was further discusswion of PTEN loss and sarcoma, OncoScan, MLN-0128 mTORC1/2 inhibitor Takeda phase II for sarcoma with PTEN loss. Plans to get biopsies to look at correlatives and working on protocol. Other directions include resistance mechanisms and combinations of PARP and aurora kinase inhibitors. Another project involves TOPO2A as predictor of doxorubicin sensitivity. Doxorubicin is standard of care in STS; older patients usually get it as a single agent. Certain cells are primed for apoptosis. Dr. Cukierman is interested in fibrosis associated with cancer. There was discussion about desmoid tumors associated with APC, beta-catenin mutations. Collapse
2-25-15

Dr. El-Deiry introduced the TRDG, welcomed the attendees at the meeting and went over the standing Agenda that was circulated in the initial invitation and in the email with the schedule for the meeting. It was discussed that various meeting formats going forward would be used including the round-table as well as more focused in depth presentations by individuals or collaborators... Expand
Coffee and cookies were available. This meeting is scheduled for every two months. It was discussed that the membership of the group will very likely evolve over time and the attendees at this first meeting were asked to suggest participation by those who may be interested. It was suggested to invite clinical or lab trainees to this meeting. Drs. James Duncan, Edna Cukierman, Josh Meyer and Penny Anderson were suggested to be included in this group. The participants of the meeting spoke about their translational research interests. Dr. Meg vonMehren who is a clinical oncologist and clinical trials investigator has worked on GIST. Currently at FCCC there are no trials open for GIST but she is working on a concept with a demethylating agent. There is a fellow involved and she has discussed the concept with Dr. JP Issa to try to get funding. She is also working on a protocol that uses Gleevec plus an Akt inhibitor. Dr. El-Deiry mentioned that Saladax will be visiting FCCC in a few weeks to present at a noon-time conference and will be meeting with various faculty who may be interested in PK-guided dose adjustment and population heterogeneity of drug metabolism. Saladax has tests for 5-FU, Gleevec, Paclitaxel and Docetaxel and is currently doing drug level testing for free. Dr. vonMehren spoke about aging effects, toxicity and dosing of Gleevec so there may be opportunities. Dr. El-Deiry mentioned that such drug testing that leads to dose adjustment in the context of clinical trials is low hanging fruit for improving therapeutic clinical trial accrual especially when combined with correlative science. Dr. Sujana Movva is a clinical oncologist who works collaboratively with industry looking at genomics. She mentioned collaborations with Caris Life Sciences and Castle biosciences looking for who is more likely to metastasize. She mentioned two clinical trials concepts that have been approved through industry including: 1- Novartis, 2- Takeda with mTOR inhibitor for PTEN loss that occurs in some sarcomas. She presented data at ASCO last year including from the genomic analysis through Caris that helped evolve the trial concept. Dr. Pei is doing CGH and collaborating on analysis of sarcoma with PTEN loss. She mentioned an interest in combining a CDK4 plus PI3K inhibitor and is currently waiting for budget and working on protocol. There was discussion about interactions with Caris and other companies and current limitations of some of the testing. Dr. El-Deiry mentioned that Caris is working to set up a center of excellence at FCCC, and that there are opportunities to analyze clinical outcomes and correlate them with genomic alterations, and that the testing so far looks promising as far as generating hypotheses for clinical trial testing targeting subsets of patients with potentially actionable changes. Dr. Eric Ross spoke about biostatistics and informatics support and databases. There was discussion about access to tissue through the biorepository and access to tissue through pathology. Dr. Lori Rink is an Assistant Professor who has an R00 award from the NIH. She is looking at certain proteins with Zn fingers and imatinib resistance. She is interested in biomarkers of response. She mentioned a study using 80 GIST serum samples with Illumina analysis of proteins including periostin and TGFbeta. She mentioned tissues from 85 cases of GIST on a TMA and working with a clinical fellow who has clinical response data. The TMA is a great tool for the research on new biomarkers and to make associations with clinical outcomes. Dr. Rink is also doing preclinical studies with a Merck Akt inhibitor in combination with imatinib and is working to write it up. She mentioned response heterogeneity in cell line xenografts and having used an approach of RNA-Seq and hoping to also get some genomic mutation data from the RNA sequence analysis. She mentioned PDX models of sarcoma have been tough due to slow growing tumors. Dr. Marty Belinsky is a staff scientist looking at GIST doing exome-wide sequencing of wild-type GIST. He is looking at tumors that lack kinase mutations; tumors with a hypermethylator phenotype. Also looking at a case that is WT without the hypermethylator phenotype due to succinate dehydrogenase deficiency and has found a clear frame-shift in NF1, doing IHC on Max (also associated w/ pheochromocytoma and SCLC). Myc is not particularly implicated in GIST although some are amplified. Dr. Movva mentioned she had a patient with EGFR mutation (Kit, RAF, PDGFR wild-type). Dr. Jeff Farma practices surgery on GIST retroperitoneal sarcomas among other tumors. He mentioned a retrospective analysis with sarcoma. He suggested that patient and tumor heterogeneity is a big problem and that we don’t know when to radiate retroperitoneal soft tissue sarcoma as far as pre- versus post-operatively. He also mentioned that in general the cooperative group trials haven’t led to much new knowledge in this area. There is a need to get more info about numbers of patients and tissues. There was discussion about some discrepancies between what people thought and what the registry data suggests. It was mentioned that at FCCC there are tissues collected from untreated GISTs that are resected. It was also mentioned that when trials are open they accrue well. Dr. El-Deiry asked about some of the highlights as far as accomplishments in this disease over the last few years at FCCC. Dr. vonMehren mentioned involvement with a study of Regorafenib in GIST showing it has some activity and that a PDGFR alpha inhibitor was not successful. She mentioned trials of combination therapy with doxorubicin and a trial with trabectedin for 10 years and interest in phase III compared to dacarbazine as well as an IGF1R study. Dr. vonMehren spoke about possible collaboration with Dr. James Duncan to analyze kinomes as there is clearly intrinsic resistance in some GISTs and Dr. Rink mentioned there is no analysis of the type that he is doing as far as the response to imatinib. There was discussion that because imatinib has been so successful, this is limiting other avenues for research in GIST. There was mention of possible opportunity in the setting of adjuvant trials to avoid issues of waiting for imatinib to fail and interest in sutent plus Akt inhibitor as second line therapy. Dr. El-Deiry asked about immunotherapy for GIST or sarcoma and Dr. vonMehren mentioned a study of ipilumumab plus dasatinib at MSKCC for GIST and Dr. Movva mentioned that a pembrolizumab study for sarcoma is opening here at FCCC. Dr. El-Deiry mentioned there will be opportunities with the microtron in terms of early phase trials including potentially in combination with chemotherapy and that the group would benefit from input as well as interaction with radiation oncologists in this context. Dr. Movva mentioned that a data warehouse has 300 cases and the biorepository bank has about 80 sarcomas including leiomyosarcomas. Dr. Eric Ross mentioned that the kidney group has their own database and they consent patients to get samples to the biobank. There was discussion about consenting for research on tissue and issues of the amount of time to do research prospectively for a rare tumor versus opportunities through analysis of existing tissue. Dr. El-Deiry mentioned that the Nanostring instrument will be here at FCCC and there is opportunity to perform transcriptomic RNA analyses at an affordable price. The group should think about uses for this powerful tool that can analyze RNA from paraffin embedded tissues. Dr. El-Deiry mentioned a paper published in Nature in the last couple of weeks that he will circulate where a patient with metastatic breast cancer had an autopsy with extensive genomic analysis of multiple metastatic lesions and the primary tumor that identified PTEN mutation or loss as resistance mechanism to a PI3K inhibitor. He suggested thinking about a similar approach in aggressive sarcoma where new insights may emerge. Collapse

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