Esophagus, Pancreas, and Liver 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.

10-7-16

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 3^rd 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
Modern therapies are changing the face of Hepatitis C and this may impact on HCC. Dr. Denlinger discussed non-alcoholic fatty liver disease (NAFLD) related to abdominal obesity, hyperlipidemia and is currently the second leading indication for transplant. Alcohol, liver injury, PBC are other risk factors. All oral treatments with genotype 1B seeing cures in virtually all patients. 12 wks of Rx including ribavirin and other oral meds. Obesity and liver cancer are much more of an issue for men versus women as far as death rate. One issue is many patients are not getting biopsies as it has become a radiographic diagnosis. Bleeding and seeding are issues with biopsies especially if considering liver transplant. Metastatic disease is more likely to get biopsied. Dr. Denlinger spoke about the clinical management of HCC as far as chemoembolization versus sorafenib versus supportive care. The 5-year survival is 70% with preserved function; cirrhotic livers don’t regenerate as well. Patients are usually on immunosuppression. She spoke about MELD scores and survival in HCC. Transplant program is driven by Milan criteria that depend on tumor size, number of tumors less than 3 cm, vascular invasion, and distant metastases. Small tumors less than 2 cm get RFA or microwave ablation. A study at NCI is assessing immune response in liver confined disease. Drug eluting beads with doxorubicin is used. Y-90 radioembolization is less toxic than chemoembolization with similar impact on survival. Sorafenib is the only FDA-approved drug still with improvement of 2.7 months in OS, with many side effects. Sorafenib after chemoembolization did not help. The STORM trial post-transplant showed no effect on OS from sorafenib. Sutent was worse than sorafenib. Sorafenib plus doxuribicin didn’t work. Multiple others such as erlotinib, everlomius, ramicirumab didn’t work. Tivatinib in a phase 2 in high c-MET suggested a possible signal. Some data on nivolumab in refractory HCC that may be promising. Guadecitabine a demethylating agent showed good outcomes in second line. There is a fairly large liver program at FCCC and Temple. 30-45 new patients with HCC are seen annually at Fox Chase. 15 new patients with metastatic disease were seen in 2015. Most etiologies were HCV related. There are 10-20 resections of HCC per year at Fox Chase. Temple sees 30-40 new patients with HCC annually. 25 biopsied, 73 TACE, 19 had liver transplant. The Fox Chase portfolio of trials includes ECOG1208; sorafenib + ipafracept ph I (wnt inhibitor) 1^st line. 2^nd line metastatic disease PF-03446962 anti-ALK1 antibody. SGI-110 (Guadecitabine) previously as nth line. NASH patients have better liver function versus those with HBV or HCV. Dr. Denlinger discussed upcoming studies including MEDI4736 +/- tremililumab (CTLA4 inhibitor) in 2^nd line in sorafenib refractory disease, a TVEC oncolytic virus with GM-CSF trial. MSB0011359C fusion against PD-L1 and TGF-beta RII phase I with HCC cohorts. There was some discussion of possible tissue collection with embolization procedures. There was discussion of the history of the virology group at Fox Chase Cancer Center and some discussion of possible translational directions. There are 377 patients with liver cancer in the registry at Fox Chase. There was mention of a liver Foundation grant opportunity closing December 4. Collapse
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
She is beginning to combine high fat diet with DEN in these ko mice. Male mice get more liver cancer. Estrogen suppresses IL-6 and liver cancer. There is reduced IFN-gamma in IL27 receptor ko mice. She described associations with reduced cyclin D, IL-11, Foxp3, and CCL20. Fewer Tregs and less PD1 and PD-L1 with increased effector T-cells with interferon-gamma cytotoxicity. There was discussion about this being potentially a good model, unique to FCCC, with potential for use in development of unique therapeutics for HCC, as well as a model for understanding HCC in different genetic backgrounds. Dr. El-Deiry mentioned crossing into other backgrounds such as T-antigen which predisposes to liver cancer and there was discussion about MRI imaging of the mice although there are currently some technical challenges. Dr. Efrat Dotan spoke about geriatric oncology research and efforts to study CTCs in metastatic pancreatic cancer. The population is aging and by 2050 there will be 90 million 65 years and older and 20 million over 85. 60% of incidence and 70% of death in breast and CRC occurs in the elderly. At what age should screening stop? Dr. Dotan serves on the NCCN senior committee. She spoke about geriatric assessment. Hurria JCO 2011 described 10 factors that can be screened for and there’s an app for it. This assessment has potential to predict toxicity. There are a number of biomarkers of aging such as telomere length, IL-6 levels, CRP, fibrinogen, factor 8. People with longer telomeres live longer. People with shorter telomeres have increased cancer incidence and mortality. She showed some data from 2012 ASCO abstract 9011. Literature data described 5-FU toxicity in relation to telomere length. Patients with shorter telomeres have more mucositis and diarrhea. She used biosample repository tissues to look at telomere length. Of 100 patients, she could get treatment information on 30. She has a prospective study that is ongoing. Patients >70 with untreated colorectal cancer with good performance status who will get chemo get telomere length and geriatric assessment and are then followed for 6 months on therapy and then go off study and get long term follow-up. The trial design evolved due to some challenges in patient accrual and so she is now enrolling both adjuvant and metastatic, now enrolls >65 yo. Was enrolling FOLFOX but now enrolls if getting any chemotherapy. The measurement is a PCR-based test to get telomere length.
Has analyzed >300 samples from biosample repository. If study has signal from telomere length she is considering a cooperative group trial including CRP, IL-6 measurements. She has an ongoing study in breast cancer with measurements of p16 PBTL mRNA. There is data for increased p16 levels with aging, frailty. Dr. Neena Vijayvergia working with Dr. Dotan has collected data from patients with metastatic pancreatic cancer; N=579 database with all treatments. 299<65yo and 280>65 yo. Overall survival by age at Dx was not diff between the two groups. Treatment helps in older patients. Older patients were less likely to receive more than one agent. Work is leading to prospective trials in pancreatic cancer therapy in elderly patients. Will compare Gem/abraxane vs FOLFIRINOX toxicities in the elderly. Collapse
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 4^th 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
He spoke about Olive et al in Science, 2009 that predicted gemcitabine + Shhi would work in pancreatic cancer but it ended up not working as a strategy in human testing. STA8666 looks good in KPC in terms of prolonging survival (Skobeleva, Khazak). He did an experiment in a PDX model of a pancreatic tumor with a myc amplification with STA8666 that drove the tumor into remission. He showed a second PDX model with remission and mentioned others where it is better than irinotecan. Of 4 PDX models tested the drug caused 2 remissions and 2 with response that was less complete, with suggestion that not all tumors respond. Dr. Chernoff asked about HSP90 in stem cells, and Dr. Astsaturov mentioned a literature exists on this and there is some interest at FCCC in targeting HSP90 in cancer stem cells. There was discussion about issues of patient selection and patient heterogeneity. At this time Drs. Astsaturov and Boumber plan to test all comers in early trials but subsequently there may be focus on specific cohorts. Dr. Astsaturov spoke about FAP targeted delivery to pancreatic stroma; Drs. Cohen and he spoke about a tripeptide that was toxic in patients in early clinical testing. Dr. Astsaturov showed data from a Pancreas, 2008 publication by Dr. Cohen where fibroblasts surrounding tumors were found to express FAP highly. Dr. Hoffman spoke about work in Seattle where fibroblasts appear to mediate metastases. There is interest in whether the drug gets to the fibroblasts. Dr. Astsaturov spoke about FAP activity in fibroblasts and their FAP activity (work of Dr. Kathy Alpaugh). He wants to use the fibroblasts to target the tumor. Dr. Cukierman spoke about a renal and a liver metastasis that were both very desmoplastic. So it looks good for delivery to pancreatic lesions. Dr. Hoffman mentioned that lung resection for metastases from pancreas is done. Dr. Astsaturov said PDX tumors do metastasize and said FAP has not yet been tested in metastases but this can be done. Dr. El-Deiry mentioned Dr. Kalluri’s results at GI ASCO with a direction towards classifying pancreatic tumors by extent of stromal involvement, making correlations with prognosis and moving towards bringing in immune checkpoint approaches for low stroma tumors that have a worse prognosis. Dr. Astsaturov spoke about in vivo testing using a fluorogenic probe that is an FAP substrate in collaboration with Drs. Kerry Campbell and Harvey Hensley and showed tumor accumulation of the probe. He is collaborating with Dr. Bill Bachovchin at Tufts testing fluorogenic and pro-drugs that deliver doxorubicin or proteasome inhibitor. He described various directions targeting CSCs, imaging, CRISP/CAS9. There was some discussion about genomics and how it could help, some discussion of BRCAness and platinum sensitivity and discussion about genomic profiling the PDX models versus their responses to treatments. There was some discussion about neoadjuvant Rx and resectability with FOLFIRINOX or gem/abraxane combinations. Dr. Cohen mentioned there was interest in this at FCCC years ago and may be there are some opportunities going forward. Dr. Astsaturov mentioned that Myriad has a test of bracaness looking at rearrangements looking for HR proficiency. Dr. Einarson mentioned the high throughput core has a gamma-H2AX assay that is also available for investigators interested in drug sensitivity and DNA breaks in a different kind of assay. Dr. Esnaola spoke about the FCCC catchment area. There are 15 counties in PA and NJ that capture 80% of our patients. He mentioned the top 5 cancers are prostate, lung, breast colon, bladder account for 56.8%. The top 5 as far as death rates: lung, CRC, breast, pancreas, prostate. He showed that mortality varies by region and mentioned superfund sites with dye, epoxy, aniline dyes that may explain some of the increased bladder cancer. He described socio-demographics, cancer incidence rate ratios, mortality rate ratios, and went over race, ethnicity effects on incidence or mortality. Trends could be explained by biologic versus access to care differences. There was further discussion about social determinants and obesity effects. Collapse
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
There was question about VDR KO. AML/ETO is transdominant mutant that can bind and neutralize VDR function. Dr. Yen looked at transcriptomes of VDR KD vs. control and found altered expression of various targets. He showed that sensitization to gemcitabine is not due to checkpoint override because the VDR KD cells do not enter mitosis and they die in S phase (they die in M with Chk1 siRNA plus gemcitabine). VDR KD delays and reduces Rad51 gamma-H2AX foci formation that is expected to reduce homologous recombination. Dr. Yen is collaborating with Dr. Neil Johnson to test the prediction that VDR KD cells would be sensitive to PARP inhibitors if cells are deficient in double-strand break DNA repair. In the clinic if targeting VDR can enhance sensitivity to gemcitabine through such a mechanism involving double-strand break repair, it may also sensitize to PARP inhibitors. He did more mechanistic experiments in VDR KD cells and showed that an HDAC inhibitor TSA restores RAD51 foci after gemcitabine. By contrast KD of p300 resulted in loss of Rad51 foci. P300 KD sensitizes pancreatic cancer cells to killing by gemcitabine. VDR is expressed in virtually all pancreatic cancer cell lines. Also PDX models from FCCC express lots of VDR. There may be use to correlating VDR with likelihood to response to gemcitabine in human tumors. There are TMAs that Drs. Cukierman and Hoffman are already testing for responsiveness to gemcitabine. Additionally, Dr. Yen has plans for mechanistic studies. There was some discussion about heterogeneity of VDR in human tumors and this is not yet known. It is also not known if the newly recognized VDR repair pathway is functional in other cancers and this is an important question. Dr. Yen spoke about VDR-mediated stromal reprogramming that suppresses pancreatitis and enhances pancreatic cancer therapy (Sherman et al. Cell 159:80, 2014). There is a current clinical trial at Penn that is testing this a vitamin D agonist that can impact on the stroma. He thinks there is an unknown ligand that binds VDR in his system (ligand X) and that this vitamin D agonist may ultimately compete with ligand-X. There was some discussion that VDR controls EMT; low VDR promotes mesenchymal phenotype. There was discussion about various strategies of sensitization including radiation, Microtron. There was discussion about strategies to bring the new findings to the clinic including by trying to demonstrate in vivo that VDR blockade may allow sensitization of innate or acquired gemcitabine resistance. It was pointed out that gemcitabine is now combined with abraxane for patients who can tolerate it and so this needs to be considered in experimental design. Due to the extensive discussion it was decided to postpone Dr. Astsaturov’s presentation till the next meeting. We would try to find a date where Dr. Steve Cohen could participate in the meeting as well. Collapse
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
They would like to do a prospective study and evaluate lipid levels, tissue, etc. Dr. El-Deiry spoke about healthy platforms, showed brief video. Dr. Fang will follow-up with Charlie Coltman. Dr. Kerry Campbell is an immunologist who works on NK cells. He is working on mice with pancreatic ca. Worked with Dr. Peter Adams. Dr. Scott Lowe at MSKCC has shown that NK cells eliminate senescent cells and those that survive may form tumors. PDX1-Cre KRAS G12D develops senescent cells early and develop cancer at 12-14 months old. Crossed to Rag-deficient that are deficient in B and T cells. IL2-R gamma mice have NK cell deficiency. DKO had increased p16 and decreased Ki67 in pan-in regions. Cause of death of mice not exactly clear and many did not have tumors. Did IHC looking for NK cells within pan-ins. NK cells with GFP. But background fluorescence is high. Stained for GFP and found NK cells in veins more than would be expected. Worked with Dr. Ramirez at Temple and looked at pancreas pieces and founds tracks of NK cells going into the pancreas. Has interest in finding out what is attracting NK cells. There was discussion about the recent Vogelstein paper in science that associated the number of life time stem cell divisions with cancer risk and gene mutations. Dr. Eric Ross spoke about work with Dr. John Hoffman who had patient outcomes. He suggested the group may want to keep that database going. Dr. Crystal Denlinger talked about efforts to continue to update the database of 100 patients with pancreas cancer who had surgery and chemotherapy, CA19.9. Dr. Ross mentioned samples from Hepatitis project that relates to HCC. There was P01 funding with foreign >100K patients and a Philadelphia cohort. Data hasn’t been used for >10 yrs. Dr. Alison Evans at Drexel was epidemiologist. Patients developed liver ca. Had baseline blood collected. Dr. Denlinger spoke about the face of hepatitis as changing and there are opportunities to compare drugs/embolizations/antiviral therapies to the era when none of this was being done. One issue is that in modern times there is often less tissue so this may be more easily done in patients who had surgery. Dr. Ross will be looking into numbers of patients with Hepatitis B and C who were resected and whether there is tissue at FCCC. Ethnic differences Asian more Hepatitis B; non-asian Hepatitis C. Pathology at Temple should have a database and tissue and it may be possible to determine Hepatitis status with molecular tests. We don’t know if Hepatitis B vs C liver cancer have been compared. Cristoph Sieger is an expert who knows about this. Is hepatoma assoc w/ NASH different from Hep C? Potential opportunity to explore whether non-viral hepatitis is more relevant to our catchment area. It was mentioned there is a redcap database with outcomes for patients from surgical complications. There was discussion about whether there are extremes in response of pancreatic cancer to therapy that could be investigated? Gem/abraxane/folfirinox living greater than one year. There are 45 patients in the database who did not relapse. All are adenoca (a few w/ IPMN w/ invasive tumor)—all adenocarcinoma. What about BRCA2 and familial pancreatic cancer. Dr. Cooper mentioned a possible case. There was discussion about fibrosis and its role in limiting cancer growth. There was discussion about perpetuating Hoffman’s database. There was discussion of no need for consent for de-identified excess tissue. There was discussion about availability of chromosome microarrays at the institution and potential to apply to research questions. Dr. Ross spoke about TGCA and whether this is available for pancreas. You can download a dataset. Can request outcomes. Data is freely available. Access to clinical data is not onerous. Several investigators at FCCC are using TCGA. It was suggested to include Drs. Margaret Einarson and Andreas Karachristos in this group. Collapse
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
It is also desirable to meet in a room with video-conferencing capability and the conference room in the lower level of the Young Pavilion (Radiation Oncology) was suggested as a potentially good venue. 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. The participants of the meeting introduced themselves and spoke about their research interest. Dr. Crystal Denlinger is interested in GI cancers, early phase UGI malignancies, GE junction tumors and Her2 + tumors. She has been collaborating with Tim Yen on pancreatic cancer. She also sees patients with HCC and has a focus on cancer survivorship in GI cancer and has a study being presented at GI ASCO. Dr. Alana O’Reilly is a member of the Cancer Biology Program and has an interest in stem cells in fruit flies, dietary changes influences on stem cells, the hedgehog pathway in pancreatic cancer in collaboration with Drs. Edna Cukierman, Tim Yen, and Igor Astsaturov. Cholesterol has a major influence and hedgehog is a marker in pancreatic cancer. Dr. Carolyn Fang is doing a population science study checking behavioral responses to drugs versus nutritional factors. The Bucks County Board of Associates is supporting a Nutrition Seminar at FCCC to connect the public. Dr. Margaret Einarson is a basic scientist who is interested in technological bridging. She manages the HTS screening facility that has a whole genome siRNA library, assesses drug responsiveness, has libraries and has high content imaging. Dr. Tim Yen is a member of the Cancer Biology group with an interest in pancreatic cancer. His group identified the vitamin D receptor to be a novel survival pathway in pancreatic cancer and as a drug resistance mechanism. His group does chemical library screening to repurpose kinase inhibitors that are FDA approved. He has worked with Bosutinib (not dasatinib) that targets src and has collaborated with Dr. Crystal Denlinger on a clinical protocol for Pfizer to combine the wee1 and chk kinase inhibitor to sensitize to chemotherapy in a strategy that involves Gem/Abraxane with drug as a chemosensitizer. They will be looking at PBMCs and tissue. Dr. Valentine Robu is involved. Dr. Efrat Dotan is a GI medical oncologist who is involved with many clinical trials including developmental therapeutics/phase 1 studies in pancreas and colon cancer. She studies elderly patients and their response to therapy; factors that predict response to Rx; telomere length as predictor of toxicity. She mentioned a wee1 inhibitor combined with gem/abraxane trial with experience in several patients. Dr. Crystal Denlinger mentioned gemcitabine toxicity was a factor contributing to LFT abnormalities. There was some discussion about dose levels. Dr. Tim Yen auggested that because both kinases are inhibited this may require lower doses. Dr. Edna Cukierman does basic research on the TME using a 3D system and studying the heat shock pathway, fibrotic responses; some in collaboration with Dr. Alana O’Rielly and also looking at human material. She is also collaborating with Dr. Caroline Fang as well as Drs. Tim Yen and Alana O’Reilly in a pancreas cancer group. There are collaborations with pathologists on microarrays, as well as collaborations with Dr. Igor Astsaturov on PDX models and collaborations with Dr. Kerry Campbell. Dr. Andreas Karachristos is doing surgery such as liver resections, and interested in growing livers to ameliorate ischemia-reperfusion injury. He spoke about portal flow and effects of drugs such as somatostatin analogues. Dr. Elena Shagisultanova is a 3^rd yr fellow in Hem-Onc who was a post doc at Burnam (worked with Manuel Perucho) and has experience in clinical research working with Dr. Erica Golemis in proteomics; has an interest in translational research. Dr. Igor Astsaturov is focused on pancreatic cancer translational research including PDX models and recently in the role of cholesterol transport in tumor growth and therapy. There is an HCC working group that meets once a month with a critical mass There is an interest in second line therapy in HCC (after sorafenib). There is an interest in the stroma in the liver. There is an interest in survivorship issues and there is a survivorship group. Dr. Karachristos discussed the importance of fresh tissues and blood; and the use of the biosample repository. At $40 per sample can get both FFPE or fresh tissue and this includes deidentified clinical data, and QA is included. It was mentioned that Dr. Ross can help deidentify samples. It was mentioned that there are separate consents for clinical trials and the biosample repository. There was some discussion about some obstacles in accessing tissue and there was clarification that ultimately the clinical data is available and investigators can do what they need to do through the pathology department or the biosample repository if they write an IRB protocol that explains there need and their planned use of tissue. The Protocol Support Lab keeps tissue, and there is tissue in pathology. There was discussion regarding the merits and currently as a hot topic of analyzing extreme outliers, i.e. patients who have had complete responses unlike most patients who were treated in the same way. There was discussion that there is currently no capability to do PK at FCCC on an investigator initiated protocol and that this is an issue that needs to be addressed to facilitate drug development translational research. There was some discussion of genetics and genomics. Dr. Michael Hall mentioned there is an MMR database and that expanded genetic testing is currently being done. There was discussion that access to molecular data from the registry has been difficult but now being captured. There are lots of unusable data and lots of data that is not captured. There was discussion that these are issues to be discussed with Dr. Ross in bioinformatics through involvement with the committee that oversees the databases and research needs. There is a data warehouse for survivorship; smart-phrases in Epic can retrieve patients but there is a need for efforts to populate databases. Collapse

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