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. This meeting is scheduled for once a month and at present this is a Tuesday. It is expected that meetings will focus more on Kidney or bladder or prostate cancer, 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 the 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... Expand
It was discussed that we may want a slightly bigger room given that this meeting was already exceeding the size of this conference room. 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 initially introduced themselves giving a few words about their research interest. Attendees at the start of the meeting who introduced themselves: Dr. Dan Geynisman (described activities in Oncology trials, survey based research), Dr. Warren Kruger (described interests in metabolism changes in cancer), Dr. Eric Horwitz (focus on prostate & bladder clinical trials),
Dr. Tahseen Al-Saleem (urologic pathology research), Dr. Vladimir Kolenko (work on TKI resistance, natural products), Dr. Mary Daly (genetics), Dr. Michael Hall (genetics of prostate and kidney cancer), Dr. Erica Golemis (signal transduction, Polycystic Kidney disease and kidney cancer and analysis of sequencing in collaboration with Dr. Betsy Plimack, Dr. Hyung-Ok Lee (works with Warren Kruger on kidney cancer hydroxychloroquine and amino acid profiling in patients, Dr. Phil Abbosh (genomic analysis of urine from bladder cancer patients and interest in kidney cancer), Dr. Edna Cukierman (basic research on the extracellular matrix some in collaboration with Bob Uzzo). Genetics and Database: Dr. Mary Daly mentioned that one of the strengths at FCCC is the Database and the excellent patient base. The Kidney data-base is exceptionally strong and this was facilitated by the prior Keystone Program in Kidney cancer. It was mentioned that a database started with Jerry Hanks for high risk prostate cancer patients and is now adding family members as well. Blood samples and tissues are available. FFPE tissue. In the risk database only probands are included with tissue and blood. TMAs have been used. Someone mentioned a study looking at Myc staining. There is genetics information on all renal cancer patients with some follow-up. It was mentioned that a weakness is clarity on whether patients are still alive, and the sequence of therapy is not always clear. There was discussion that a deidentified database can be a great resource for cohort discovery and it was mentioned that the kidney keystone helped build the two deidentified databases. Serum amino acids: Dr. Warren Kruger mentioned serum amino acid profiling with kidney cancer. It was expected that profiles would normalize after surgery, however that was surprisingly not the case. Thus his group is asking whether there may be a genetic basis. Serine and alanine were found to be low. Some patient had their serum sample measurement 2-3 months after surgery. F1000 picked up and reviewed the published story. There was some discussion and it was mentioned that there is a goal to determine specificity, i.e. whether this is kidney cancer-specific or whether similar things may occur in prostate, lung, bladder cancer, etc Dr. Kruger is interested in a prospective study and there was some discussion about potentially going to families for unaffected individuals in those with genetic risk.
Dr. Michael Hall mentioned there are 10 kidney cancer syndromes that are rare (most people know about VHL but there are clearly others) He mentioned involvement of PTEN, SDH and other genes. Dr. Mary Daly asked about smoking status and relation to amino acid changes since smoking is a strong risk factor for kidney cancer and may continue beyond surgery. Dr. Phil Abbosh mentioned that 20-30% of patients who have masses removed have benign tumors. Dr. Joe Testa mentioned he has serum from mesothelioma patients and that it would be of interest to see if they have amino acid changes. It was mentioned that FCCC has a population science interest in smoking. Dr. Tahseen Al-Saleem suggested doing lymphomas. There was some discussion about resources that have historically supported kidney cancer research and it was felt that the 50-65K for pilots that was in place did have impact in terms of ROI. Some funding was obtained through this prior support. It was mentioned that Dr. Sid Balachandran got an IIT with Dr. Dan Geniysman on Bortezomib plus IFN. Dr. Edna Cukierman mentioned she has been looking at stroma and has found it is predictive in kidney cancer with worse outcomes correlated with activity of an actin-binding protein. In Dr. Igor Astsaturov’s PDX model the mouse stroma takes over and Dr. Cukierman mentioned they will try to inhibit stromal activation. Can the stroma be normalized? A feasible experimental strategy involves inhibition of alpha-v-beta 5 through an antibody. It was discussed that there is no good mouse model for kidney cancer. Dr. Astsaturov has a relationship with Champions Oncology that can facilitate studies. There was some discussion about the clinical care of patients with kidney cancer including patients with advanced metastatic disease and the adjuvant setting. Dr. Phil Abbosh mentioned there has been a follow-up study to the NEJM describing intra-tumoral heterogeneity. In the follow-up paper in Nature Medicine there were 10 patients and the study included dendrograms with involvement of VHL, PBRM1, BAP1. An open question is whether PD1 therapy in kidney cancer may help before or after other therapy.
FCCC has a phase III trial with Ipilupumab versus Sunitinib as 1st line therapy for metastatic kidney cancer. It was suggested that Dr. Kerry Campbell who does immunological studies would be good to include as a member of this group. There was discussion that PD1 level preoperatively or PDL1 expression may be predictive of response to immune checkpoint targeted therapy based on Nature papers from last week that also showed TIL expressing PD1. However a recent JCO paper using Nivolumab was mentioned that casts some doubt over how well the expression may predict outcomes. Foundation testing is being done at FCCC although not for clear cell cancers. The problem of off-label use was discussed as far as reimbursement for drug costs and that this is a big problem. There was some discussion about how do you define actionable targets. Foundation now will fight for the patients. People are paid to appeal denials. Dr. Mario Bilusik mentioned a patient with Bladder cancer who was surprisingly found with a VHL mutation and was treated with pazopanib with response. There was discussion about the decreasing costs of genomics and issues with data. 23&Me charges $99 for 700 SNP’s. How can this data be used? Foundation can look at germ-line signals. Dr. Michael Hall mentioned that Foundation has sequence data on about 500 kidney cancers with 260 loci and they have shared germ-line data. There was discussion that drug resistance is very common. Dr. Warren Kruger mentioned hemolytic anemia and asked whether this is common with Avastin or anti-PDL1 therapy and it was mentioned that autoimmune phenomenon are not uncommon. There was some discussion about direction especially for a group with some critical mass. It was mentioned that the Kidney keystone recruited people who were interested in getting into kidney cancer and that at the present time there is a need for leadership and vision for SPORE. There is a need to determine whether there are projects that are translational that rise to the level of a potential SPORE project. It was mentioned that Dr. Rob Uzzo has some projects that involve surveillance, and anatomic complexity in surgical research. There was some discussion regarding the potential to investigate responders versus non-responders and what the typical patient gets and how they respond. It was mentioned that 1st line therapy currently involves either pazopanib or sunitinib based on comorbidities and tailored for good risk. Axitinib is used in second line, then mTOR inhibitors. FCCC has not been focused on drug discovery for GU malignancies but rather on using other people’s drugs. In addition to Dr. Kerry Campbell’s immunology expertise, Dr. Joe Testa has expertise with mTOR and Akt pathways and Dr. Peterson’s chemical biology expertise may help sort out specificity of TKIs. There was discussion of metastatic kidney cancer and the availability of biopsies as well as tissue from nephrectomies. There was mention of the work of Brugarolas from Dallas and that his web site shows some promising capabilities. There was further discussion about P01 and SPORE opportunities and that the group will need to revisit how to work towards these as goals. There is need for input from Dr. Betsy Plimack and scheduling issues will be worked on. There are efforts to develop mouse models that are in progress. Are their opportunities with Geisinger? It was suggested to ask Dr. Bob Beck to invite someone to discuss FCCC potential access to their resources and that we need to learn more and think about how we might work with them. Need to engage more colleagues at Temple and there was mention of Periera (GU). Nanostring is something that may add value that may be amenable for single cell analysis. Collapse