Colorectal and SI Cancer TRDG: Meetings and Minutes


  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.


CRC-SPORE Investigator meeting. Dr. Chernoff presented an update on “Targeting the Kinome in KRAS Mutant Colorectal Cancer Project.” 


CRC-SPORE Investigator meeting. Drs. Clapper and Cooper presented an update on “MicroRNA Signature for the Detection of Flat and Polypoid Colitis-Associated Colorectal Neoplasias Project.”


CRC-SPORE Investigator meeting. Dr. Waldman and Weinberg presented an update on “Preventing Colorectal Cancer in Familial Adenomaous (FAP) Project.”


Dr. James Duncan spoke about “Targeting the kinome in K-ras mutant colorectal cancer”. He described the human kinome, the kinome screen he developed and published in Cell when he was at UNC and discussed questions regarding resistance and creating new therapy options. There was discussion about approaches for acquired versus intrinsic resistance to therapy. Dr. Duncan spoke about dynamic reprogramming that involves a rapid change in other kinases to allow cancer cell survival and that he is evaluating this in the context of various drivers. Dr. Duncan went onto details of specific therapies where reprogramming is involved. He described in detail his assay for proteomic profiling of tumors. He spoke about KRAS in CRC and mentioned work by Kevin Shokat at UCSF with KRAS G12C and a specific therapy targeting that mutant. Dr. Duncan described efforts to profile the kinome in cells with different mutants and their potential impact on kinome reprogramming.


Dr. Nestor Esnaola spoke about the “Effect of Metabolic Syndrome and its Components on Recurrence and Survival in Colon Cancer Patients”. He described use of SEER data and mentioned cardiovascular risk factors associated with insulin resistance and metabolic syndrome. He defined metabolic syndrome and mentioned that 1/5 of adults have the syndrome and that almost all diabetics have the syndrome. Some components are more relevant to cardiovascular risk; insulin resistance, diabetes, obesity, inflammation. Hotamisligil, Nature, 2006 reviewed the relationship between inflammation and metabolic syndrome. Various cytokines IL6, TNF and adipokines Leptin and adiponectin are involved. Dr. Esnaola mentioned that there is an obesity epidemic that is world-wide including 66% in US who are overweight... Expand


Dr. Niklas Finnberg spoke about establishing normal and cancer organoids. The success rate is low (10-15%) for establishing 2D culture of human tumors. The success rate is higher for 3D culture (71% from biopsies ~90% from resected tissue). The PDX success rate is 23-75% but takes 6-8 months to establish. The take rate in PDX is higher for metastatic lesions than primary tumors. Organoids have been generated from multiple tissues. Dr. Finnberg reviewed organoid culture results from Clevers in Nature in 2008. R-spondin binds lgr4, 5 and activates wnt signaling. He showed growth of intestinal organoids and potential for genetic manipulation with p53F/F appeared to have growth advantage in the context of an organoid. Colonic crypts are much more difficult in plating (1-3%) versus small intestinal organoids (90%). ALK, p38 inhibitors and wnt3a supplementation has been reported by Clevers in Gastroenterology 2011. Current media for organoid culture is complicated with >15 components including valproic acid, PGE2, Rho kinase inhib, Noggin, EGF, Gastrin, Pen/strep, DMEM, Glutamax, wnt3A conditioned media, R-spondin, A83-01, SB202, CHR99021, B27, NAC, HEPES. Dr. Finnberg described a colon cancer from a patient with juvenile polyposis where normal organoids and tumor tissue was cultured. Tumor tissue culture leaves out wnt3a. The Clevers Cell paper from 2015 described prospective derivation of a living organoid biobank of colorectal cancer patients. This paper showed histology of the tumor organoids. They tested 81 drugs. Correlated KRAS with poor cetuximab sensitivity. There are sensitivities without genetic biomarkers. This paper didn’t correlate clinical outcomes with organoid sensivities. There was discussion on Znf43 that can be mutated and is also seen in pancreatic cancer. The Tuveson lab has made correlation between organoid sensitivity with sensitivity to drugs in patients. There was discussion of results from FCCC where normal and tumor organoids were established and general discussion of feasibility and plans going forward.


Dr. Joshua Meyer spoke about genomic analysis and the impact of age on CRC development. He described his previous work (Meyer, Cancer, 2010) where he observed increasing rates of rectal cancer in young people (under age 40) but didn’t see that for colon cancer. The rates of rectal cancer have been increasing since 1985. More recently (Meyer, JNCI, 2015) looked at lymph node status by age. The younger patients with rectal cancer were more likely to have positive lymph nodes. There is a correlation with worse survival with more positive lymph nodes in all age groups. Similar trends were observed with more lymph nodes in younger patients with colon cancer. Dr. Meyers referred to TCGA, Nature, 2012 looking at hypermutated tumors versus non-hypermutated tumors. TGF-beta and BRAF enriched in hypermutated tumors while IGF2, miR-483 were upregulated in non-hypermutated cancers. Dr. Meyers described ongoing collaborative analysis in colon versus rectal cancers and differences between younger versus older patients. He also mentioned CGI-066 assessing intra-tumoral heterogeneity and chemo-RT response in locally advanced rectal cancer utilizing DNA sequencing and PET/CT. 17 accrued, 13 analyzed and he presented preliminary findings. Plans include collecting 40 patients looking for response to chemo-RT.


There was discussion of an NCCN grant submission opportunity and discussion about EPCRS. Dr. El-Deiry provided an update on the CRC-SPORE with action items including contact with the NCI and working with the grants office to have a clear timeline for the document. Dr. Finnberg introduced his interest in checkpoint kinases and interest in targeting checkpoint kinases to impact on the toxicity of chemotherapy. 


Dr. Alfonso Bellacosa spoke about DNA repair and translational directions. DNA repair prevents accumulation of mutations in cancer. DNA repair affects methylation as well. He spoke about gene discovery via exome sequencing of high-risk families and presented some data on families in Italy with colon cancer and other rare tumors. MED1 and TDG are involved in mutation avoidance for mutations that arise from deamination of methylated-C. MBD4/MED1 are frequently mutated in MSI tumors. He spoke about contribution to genomic instability MDB4 plus MMR defect leads to a significant rise in C-to-T transitions. TDG is involved in demethylation in addition to mutation avoidance. TET1 is also involved in demethylation. Dr. Bellacosa hypothesized that defects in TET1 or TDG could lead to hypermethylation. Alterations in TET1 are very frequent in CRC. He described biomarkers that are seen with TDG defects. He presented additional results in mouse models. There was some discussion of potential translational directions using biomarkers as well as strategies targeting vulnerabilities in cancer.


CRC-SPORE External Advisory Board Meeting. Dr. El-Deiry presented the Program Schematic and Administrative Structure, Advisory Boards, Funding Base, and an overall Program Overview. There was discussion of candidate projects and Cores including Project 1 Targeting c-MET in BRCA-mutant colorectal cancer: El-Deiry, Olszanski & colleagues, Project 2 Clinical implications of microbiome heterogeneity in colon cancer: Issa, Sigurdson, & colleagues, Project 3 Targeting the kinome in KRAS mutant colon cancer: Chernoff, Cohen, Duncan & colleagues, Project 4 MicroRNA signature for the detection of flat and polypoid colitis-associated colorectal neoplasias: Clapper, Cooper & colleagues, and Project 5 Paracrine hormone hypothesis of colorectal cancer: Waldman, Weinberg & colleagues as well as Project 6 Dependence receptors and colorectal cancer: Grady & colleagues. Dr. El-deiry presented Core A Administration, and Core B Biostatistics and Bioinformatics was presented by Ross & colleagues, and Core C Pathology was presented by Connolly, and Cooper. Several candidate Career Enhancement and Developmental Projects were presented including Career Enhancement Project 1 Immunotherapy of CRC via next generation BiTEs: Robinson, Developmental Project 1 Alteration of DNA demethylation in CRC: Epigenetic biomarkers and implications for therapy: Bellacosa, Developmental Project 2 Role of Rpl22 loss in promoting colorectal cancer development and treatment resistance: Wiest, Career Enhancement Project 2 Tumor microenvironment, tumor elicited inflammation and colon cancer: Grivennikov.


This was a multi-investigator P01/SPORE planning meeting. A number of basic investigators met to discuss the prospects of organizing a P01 or SPORE in the area of colorectal cancer. Present at the meeting were Drs. Wafik El-Deiry, Jon Chernoff, Margie Clapper, Jean-Pierre Issa, Carmen Sapienza, Sergey Grivennikov, Matt Robinson, and Alfonso Bellacosa. After some group discussion, it was agreed that we may be in a better position to compete for a SPORE grant although the possibility of a P01 grant will continue to be pursued. It was acknowledged that a SPORE program would nucleate the largest numbers of investigators in multiple disciplines and could spin off various other types of grants. Dr. Matt Robinson stated that he has not worked on colorectal cancer but that his focus on antibody engineering and modifying structures to improve the efficacy of antibody therapeutics could be quite relevant. He has collaborated with Dr. Carl June to develop bispecific antibodies on a DOH grant to redirect T-cells to a tumor. The antibodies bind human reagents. His goal is to reconstitute mice with human antigens. He is collaborating with Yi Zhang at Temple. Dr. Carmen Sapienza is interested in biomarkers for CRC designed not by looking for cells or DNA in blood or fecal matter... Expand


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. Coffee and cookies were available. 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 include Dr. Michael Yu and Dr. Olszanski in this group. Attendees at the meeting described their translational research directions. Dr. Sergey Grivennikov is an Assistant Professor interested in how inflammation is connected to cancer. His work has been done in 2 different models of colon cancer including a colitis-associated cancer model and a spontaneous model with APC inactivation with adding of KRAS or p53. Hasn’t done much with human material. Inflammatory responses may be induced by microbiota and so use of antibiotics may impact on the inflammation. Dr. Girivennikov has done sequencing of microbiota in mice... Expand

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