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Esophagus, Pancreas, and Liver Cancer TRDG: Meetings and Minutes

Agenda:

  1. 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.
  2. Opportunities for collaboration based on existing ongoing activities or through knowledge of developments in the field.
  3. To exchange information regarding funding opportunities.
  4. To consider multidisciplinary programmatic efforts that may be supported by P01s or SPOREs.
  5. To discuss progress that is being made through more focused presentations by specific investigators or subgroups.
  6. 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.
  7. 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.

10-7-16

Dr. Neena Vijayvergia spoke about “Profiling in Neuroendocrine Tumors (NETs).” She mentioned there is a rising incidence of this rare tumor 5/100,000 over the last 40+ years. More are being diagnosed due to more imaging. There are 137,000 people with neuroendocrine tumors in the U.S. She described a new Gallium Dotatate Scan that only binds to octreotide-avid regions. FDG doesn’t light up with neuroendocrine tumors—they don’t take up sugar more than surrounding liver tissue. She spoke about evolution of therapies, chemo, biologics, and peptides. The neuroendocrine tumors secrete hormones. Telotristat (a tryptophan inhibitor) is a new analogue for patients who have failed octreotide; still going through the approval process. Chemotherapy is the mainstay for the poorly differentiated tumors (>20% Ki67+).  MGMT deficiency may boost response to temozolomide. Igor Astsaturov published a report in 2014 of imatinib treatment for kit activating mutation in a patient with neuroendocrine carcinoma. Dr. Vijayvergia published in the British Journal of Cancer recently on a “cancer code” study of neuroendocrine tumors.  Mutations were more rare in non-pancreatic NETs and mutations were more common in the poorly differentiated NETs.  P53, Ras seen also most commonly in the poorly differentiated NETs. None were germ-line for the tumor suppressor genes. P53 mutations correlated with poor survival including in those with well-differentiated NETs who had an aggressive disease course. There was discussion of involvement of various genes in PNET including MEN1, DAXX, ATRX, PTEN, TSC2, PIK3CA. KIT mutation was found in 3% of PNETs. Small Intestine NETs have low mutation rate (publication in JCI in 2013). Dr. Vijayvergia has analyzed 1500 neuroendocrine tumors sequenced by Caris and looked at druggable mutations. She mentioned that clinical trial GI-078 just opened at Fox Chase using pembrolizumab in high grade NETs. She described directions for correlative studies and molecular analyses of high grade versus low grade tumors.

6-10-16

There was discussion of PAR-16-176, and available NCI supplements. Dr. Tiffany Hartman spoke about “The role of Cdo and dietary cholesterol in pancreatic cancer.” Dr. Hartman described work that started in Drosophila looking at stem cells in the germarium and focusing on Hedgehog producing cells and hedgehog target cells. She mentioned that starved flies have no proliferation of stem cells depending on cholesterol and described links bet dietary cholesterol and cancer. There was discussion of the role of stroma in pancreatic cancer and the story of smoothened inhibition in preclinical studies and in the clinic. There was further discussion of experiments in flies as well as the KPC mouse model.

3-11-16

Dr. Carolyn Fang spoke about physical activity interventions and pancreatic cancer. She announced that a Luminex machine is coming to Fox Chase and cholesterol is being correlated with desmoplasia, stromal indices in pancreatic cancer and that inflammatory cytokines are being tested. The group welcomed Dr. Shannon Lynch to Fox Chase. Dr. Fang provided an update about the ongoing study of physical intervention. There is interest in physical activity interventions in general in cancer. QOL can be poor and physical activity can attenuate symptoms. Yoga, strength training, cardio. CALGB 89803 showed physical activity may improve OS in stage III colon cancer. N=1264 patients followed for various outcomes including disease recurrence. Median follow-up was 3.8 years, 159/832 recurred and 84 died. HR 0.51 for >18 MET hours/week versus those with <3 MET hours per week. The study looked at different activities. The protective HR occurred around 9 MET hours/week. 6 days of 30 min walking at leisurely pace = 3 MET/week. Dr. Fang spoke about a CALGB study of breast and CRC patients with telephone-based intervention. Self-selected physical activity. The intervention helped people exercise more. There are home-based programs for intervention. Walking at home is feasible for patients with advanced cancer and can improve mood. Most patients had finished active chemotherapy. There was discussion of a mouse study where running had anti-tumor effect through NK cells. Thus there may be cancer-specific benefits. One study done at Jefferson in pancreatic cancer after post-surgical resection, they started the intervention while still in the hospital; less pain, more functionality, less fatigue. There was discussion of IRB #13-023 protocol at Fox Chase Cancer Center led by Drs. Denlinger and Fang. There is focus on patients with locally advanced unresectable pancreatic cancer or metastatic disease, not receiving 3rd line palliative chemo. Patients are randomized to intervention or usual care. The intervention group gets a pedometer, a walking program manual, phone calls, and various assessments including psychological and physical functioning (6 min walk test), symptoms, QOL, FACT-Hep symptoms, as well as chart reviews, AEs, ability to tolerate treatment.

Most enrolled patients are still in front line without much cachexia. Dr. Fang gave an update on the study’s progress and some discussion about the heterogeneity in treatment regimens in pancreatic cancer. There was discussion about increasing sample size and considering enrollment at Temple.

1-8-16

Dr. Igor Astsaturov spoke about pancreatic cancer; mice and human translation. He mentioned IRB 12-822 protocol that has allowed 200+ implantations (PDX) including 22 PDAC models, 125 DNA samples. He described methodology using Y-27632 Rho kinase inhibitor and a feeder layer and ability to perform HTS chemosensitivity testing for live-dead. He compared histology between human and mice. There is less stroma in mice tumors that are subcutaneous. He found some toxic compounds including Triptolide, and various other inhibitors (https://www.ncbi.nlm.nih.gov/pubmed/27384421). Clustering showed segregation of the pancreatic cancer cell lines derived from patients versus the NCI60. HSP90, proteasome inhibitors, protein synthesis inhibitors, DNA damaging, microtubule, metformin, TKI, cholesterol lowering drugs; across the board activity was noted but transcriptional repressors were different. Dr. Astsaturov showed impressive in vivo PDX model data with triptolide. There is acquired resistance to triptolide. Triptolide binds ERCC3/TFIIH (Titov et al., Nat Chem Biol, 2011).

A phospho-derivative of triptolide was developed in Minnesota and has gone into trials. Downregulates Myc and other factors like GATA3, JUN, FOXO3, EGFR, MSH6, CDKN1B, and others. He showed ERCC3 depletion reduces Myc while Myc depletion reduces ERCC3. Triptolide depletes Myc mRNA with no effect on T58-phospho-Myc. He showed triptolide efficacy versus Myc amplified PDX pancreatic tumors which appear to be the most sensitive. Further studies looked at acquired resistance to triptolide. After relapse off therapy some respond but others are resistant and grow faster and showed that Myc and ERCC3 are associated with the resistance. There was discussion regarding different directions for translation including lower dose triptolide in combination with other approved or experimental agents that could be brought into clinical trials.

10-16-15

Dr. Crystal Denlinger spoke about the liver program, working to combine with Temple program. Post-transplant patients come to Fox Chase Cancer Center as do patients with metastatic disease. Half of the patients have liver disease and are not considered as candidates for various clinical trials. The average age at diagnosis of liver cancer is in the 60’s, and the 5 year survival is 15%. The incidence of liver cancer has been rising since the 1970’s; chronic Hepatitis C, and obesity related. There have been more deaths over time as well. The most common risk factor for liver cancer in the US is Hepatitis C virus... Expand

6-4-15

Dr. Ekaterina Koltsova spoke about IL-27. She works on inflammation and developed a cancer project. She spoke about immune cells, lipids and inflammation in atherosclerosis progression and described ApoE-/- and Ldlr-/- mouse phenotypes. She described an interest in anti-inflammatory cytokines in IL-6 and IL-12 family. IL-27, a largely anti-inflammatory cytokine, signals though a dimeric receptor that is expressed on various cell types. IL27 receptor -/- mice have increased atherosclerotic plaque size. In Ldlr-/- mice on high fat diet they get increased production of several cytokines such as IL-6, IL-17A, TNF, and interferon-gamma. Several chemokines were also upregulated including CCL2, and there was recruitment of myeloid cells into plaques. She showed a 3-D movie of YFP-labeled immune cells and plaque. IL-27 can regulate PD1, PD-L1, PD-L2 and other receptors, as well as adipocytes. IL-27ra-/- mice upregulate leptin. She started a project on HCC given epidemiological data of increased liver cancer in obese individuals. NASH, DM, HBV, and alcohol ultimately contribute to liver cancer. She used a DEN carcinogen model i.p. for HCC development. IL-27 role in cancer is unknown. There is regulation by IL-27 of PD1 or PD-L1, Th1 cells, myeloid cells, CTL activation, Th9. She found reduced HCC development in IL27ra deficient mice. This was surprising given increased inflammation. She found reduced Foxp3 Tregs in tumors in the IL27rko mice... Expand

5-7-15

There was discussion of an application planned for SIG for a Luminex instrument. Dr. Carolyn Fang spoke about behavioral studies in pancreatic cancer. This is an emerging area of research. She provided an overview of 3 studies she has been involved with in this area with pancreatic cancer: 1- Psychosocial/QOL study, 2- A home-based walking intervention, and 3- Dietary cholesterol and stromal activation. There is economic value to managing patients at home but there are issues with added stress for caregivers. Poor care giving in the home has some negative financial consequences. A cross-sectional study using surveys for both caregivers and patients; collecting demographics evidence of distress, adverse events, and pain inventory. There are negative health outcomes for care-givers as well. Dr. Fang spoke about enhancing QOL through physical activity. QOL can be poor and can be impacted by physical activity. She described study in stage III colon cancer and various activities. She looked at DFS and OS; the study found better DFS with higher physical activity. Dr. Denlinger mentioned that there is less benefit in rectal cancer. One of the barriers had to do with design involving supervised exercise regimens. Dr. Fang developed the home-based walking intervention for non-surgical metastatic pancreatic cancer patients. They found a 60% study participation rate; consented 22 patients so far with goal of 50 patients. 5 of the 22 never started with 4 passing away. There was discussion of whether it would be worth it to do a KRAS/p53 mouse -/+ exercise on tumor incidence and survival. Dr. Fang discussed dietary cholesterol and cancer risk and spoke about benefits of statins. Serum cholesterol is associated with hedgehog signaling, inflammatory markers, and desmoplasia. Various inflammatory markers are being looked at including IL-6, periostin. There was a suggestion to do similar experiments in mice and mention that Dr. Tiff Hartman is doing the experiment in mice. Dr. Crystal Denlinger mentioned that the vast majority of patients are receiving neoadjuvant Rx and this is likely to impact on future study design.

4-7-15

This meeting was organized to focus on translational efforts in the area of liver cancer at FCCC. Dr. Andreas Karachristos said we need to increase our volumes for HCC in general. We have a comprehensive program and could serve NJ or central PA. Many other programs are less successful with aggressive surgery. Dr. Crystal Denlinger said we are trying to get trials going and how to collaborate with other programs. We have phase I for HCC; early phase has been a focus.  We have interest in SGI110 as nth line study. Sorafenib plus wnt inhib omp54f28 as front line therapy. Dr. El-Deiry spoke about sorafenib + mapatumumab in liver cancer that did not improve outcomes in the phase I/II clinical trial. He mentioned preclinical data on sorafenib + quinacrine. It was mentioned that Avastin and erlotinib has been looked at and that FOLFOX has potential in HCC for stable disease. Ramicirumab didn’t work although there may be a signal for the high AFP tumors that may be more angiogenic; liver failure is an issue. Sorafenib has liver toxicity. Dr. Nguyen advocates for targeted Rx. Dr. Denlinger spoke about efforts to compare subtypes of Hep B, Hep C, NASH. Caris has done genomic sequences for four HCC populations: wnt, topo, methylation driven and a 4th group. Dr. El-Deiry spoke about efforts to designate FCCC as a Caris Center of Excellence in Precision Medicine and that this will provide some opportunities for developing some clinical trials. Dr. Denlinger said she would put capecitabine plus quinacrine that will be opening in colorectal cancer at FCCC ahead of sorafenib plus quinacrine; need to know if quinacrine can be given to Hepatitis patients. c-MET not prevalent in treatment naïve, but is in sorafenib pretreated patients. Immune therapy in HCC is under investigation, with several agents nationally. There has been discussion of a Philadelphia HCC consortium which is a great idea. There was discussion of liver dysfunction and clinical trials, accrual. There is a regorafenib plus Ruxolitinib trial in colorectal cancer and some discussion for liver cancer including potentially other combinations with ruxolitinib. There was discussion about CTCs, AFP+ and discussion that there are few biopsies done these days for diagnosis. There was discussion by Dr. Joshua Meyers about starting a registry of HCC patients with tissue.

3-18-15

Dr. Edna Cukierman was congratulated for getting a grant from the DOD on pancreatic cancer Dr. Igor Astsaturov spoke his laboratory’s translational efforts in pancreatic cancer. His group is interested in new therapies such as HSP90 inhibitors, Fibroblast activating protein; FAP-targeted drug conjugates and they are also doing work on transcriptional targeting of proteins such as ERCC3, CDK7. Dr. Igor Astsaturov spoke about the development of PDX model research at Fox Chase through approved IRB protocol 12-822 to collect tissue for Avatar models. At this point there are >100 tumors mostly pancreatic that have been implanted and 1/3 grew out and have been frozen as DMSO stocks. He also mentioned the colony of KRAS/p53/Cre (KPC) mice that show a median survival of 49 days. There was some discussion and differing opinions on how well they model the stroma. Dr. Cukierman mentioned a TGF-beta model that also has a stromal reaction, and that in the field people argue about which models the stroma better. Dr. Astsaturov explained that FAP is expressed on desmoplastic stroma and so he is trying to target it. In the PDX models, the tumors show poor sensitivity to chemotherapy including gemzar, 5-FU, and others. He showed data with Triptolide that is now in phase I trials and puts these PDX pancreatic tumors into remission and this looks promising. He is working on an established collaboration for STA-12-8666 linked to ganetespib, binds tumor cells and slowly releases. He mentioned Peptidase that binds FAP conjugated to chemotherapy or protease inhibitor. He is collaborating with Drs. Proia, Golemis, Boumber, Connolly: HSP90i-drug conjugates with linker to payload. Dr. Steve Cohen asked how specific this is to tumor cells with concerns about potential toxicities but it was mentioned that toxicities haven’t been seen in mice. Dr. Cukierman asked about synergy with radiation and Dr. Astsaturov thinks very likely yes there would be synergy but clinically not likely to be useful. Dr. Cohen said irinotecan plus radiation in rectal cancer leads to lots of diarrhea. Dr. Astsaturov showed data supporting the idea that oncogenic ras promotes HSP90 activation; (data from Restifo)... Expand

2-5-15

Dr. Tim Yen spoke about the recent vitamin D receptor work published in Cell Cycle and that made national news including being featured in the Washington Post last weekend. He spoke about his siRNA screen looking for genes that promote survival to gemcitabine of pancreatic cancer. He used a sub-lethal drug dose, measured gamma-H2AX and found some genes in the DNA damage network that validated the screen but also got VDR and started studying its relevance to disease. VDR siRNA was comparable to siRNA of chk1 in terms of sensitization to gemcitabine. VDR has been studied extensively as a multidomain transcription factor. VDR binds Vitamin D, heterodimerizes with various coactivators/chromatin-modifying proteins. Lithocholic acid generated by gut flora is toxic to mammalian cells. It binds VDR and can lead to detoxification of bile acids. Doxorubicin and etoposide are also impacted by VDR. However it is not known if VDR KD sensitizes to 5-FU. There was discussion that in colorectal cancer, vitamin D appears to be protective as far as disease recurrence, and some studies have measured vitamin D levels in patients and made correlations with outcomes. Transactivation deficient and ligand-binding VDR mutants do not protect... Expand

1-8-15

Dr. El-Deiry 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. Dr. Carolyn Fang has an emerging interest in pancreas cancer. With Dr. Crystal Denlinger she has pilot support for a physical activity intervention in patients with pancreatic cancer looking at quality of life and symptoms. She would like to look at biomarkers and correlate with patient outcomes. Also with Dr. Crystal Denlinger she is doing a quality of life study in patients who have had surgery that is being presented at GI ASCO next week. She is working with Dr. Michael Hall looking at caregivers and their distress levels about prognosis and therapy, looking at their needs to develop supportive interventions. Dr. Alana O’Reilly mentioned work in flies on cholesterol and stem cell proliferation and is now looking at dietary cholesterol in pancreatic cancer patients with Dr. Eti Cukierman. TMAs and blood samples are available. Serum lipids and stromal markers... Expand

12-4-14

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 presentations by individuals or sub-groups. This meeting is scheduled for once a month and at present this is a Thursday. It is expected that some meetings will focus more on pancreas versus other sites of cancer such as liver, and it was discussed that in the future a specific site may break out into its own group. However for the time being this group will hold its meetings jointly once a month as scheduled. We may alternate between a Tuesday slot and a Thursday slot if that can be scheduled in order to accommodate maximum participation from group members who may have standing conflicts. It was discussed that we may want a slightly bigger room given that this meeting was already exceeding the size of this conference room... Expand

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