Brain 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.

9-22-16

Renata Gordon from the Zeng-Jie Yang Lab spoke about “Cholesterol biosynthesis represents a therapeutic target for hedgehog pathway associated malignancies”. The presentation focused on the role of Hedgehog in various malignancies including medulloblastoma, discussion of Gorlin Syndrome, a summary of the molecular subtypes of medulloblastoma, and targeting of shh-gli by small molecules. Novel approaches to targeting cholesterol biosynthesis were discussed along with use of preclinical models to advance translational directions.

5-12-16

Fabrice Roegiers spoke about “Control of Notch Signaling in Neural Progenitors”. There was discussion about conserved signaling pathways involving pleuripotent proliferating to differentiated quiescent states in embryogenesis and adulthood. These included BMP, Notch, Wnt, Hedgehog. There was discussion of the Notch pathway including endogenous Notch repressors (Numbm Lethal, Rab5, ESCRT complex, etc) and activators (Notch, Delta, Septins, Rab11, Wasp-Arp2/3, etc). There was additional discussion and focus on Sanpodo that depletes Notch at the membrane and regulates Notch trafficking (Upadhyay et al., JCB, 2013). Sanpodo localizes with Notch in endosomal compartments. Different phenotypes in different cells depending on whether Numb is expressed and Numb can bind Sanpodo. Numb regulates p53 by inhibiting MDM2 with a role in human cancer associated with Numb loss. Loss of Numb correlates with poor prognosis in breast cancer. There was discussion of the role of the pathways in different organisms such as flies and fish. There was additional discussion about TSC pathway cross-talk with Notch with Notch downstream of RhebGTP in parallel to TORC1 (TORC1-independent). There was mention of collaborative work with Henske and that Notch may impact on TSC tumors (Karbowniczek et al., JCI, 2010).

2-24-16

Jennifer Gordon (Temple University) spoke about “Research on JC Virus and Cancer, Animal Models, and Details about the Brain Tumor Bank with Neurosurgery.” There was an introduction on Polyoma viruses including JC which causes PML; BK associated with prostate; SV40 contamination of polio vaccine; and the Merkel cell virus. There is no treatment for JC (DNA tumor virus) or PML that occurs with immunosuppressive therapy. Tysabri and other immunomodulatory drugs, Rituximab can cause PML. PML lesions have VP1 and T-antigen. T-Ag is also seen in lymphomas. There was discussion about heterogeneity in expression in the tumor cells. Bone marrow stromal cells are infected by JCV where it can replicate. JC virus is oncogenic in rodents and non-human primates. JCV T-antigen targets Rb and p53. T-antigen can interfere with myelin basic protein transcription leading to dysmyelination. Neuroblastoma, medulloblastoma, pituitary adenoma, mpnst seen. Gliomas are seen in a primate model. There was discussion about immune response to viral antigens. Usually the patients with PML are immunosuppressed, and so don’t have much of a response. Those who do have better outcomes. There was discussion of results in animal models including some work on stem cells. There was mention of a brain tumor bank with Dr. Michael Weaver, PI at Temple. This includes deidentified, formalin fixed tissues and some are also snap frozen. There are ~100 samples collected since 2005 mostly GBM (27). Some recurrent tumors. Astrocytomas (6), Oligodendromas (9), Schwanomas (5), meningiomas (13), neuronal (5), ependymomas (7), metastases (21). Patients were consented to allow recovery of clinical data.

12-10-15

Stephanie Weiss spoke about current directions in brain cancer. A brain tumor service has been organized with a navigator, a medical oncologist (Movva), a radiation oncologist (Weiss). A radiosurgery database has been created. There was mention of approval for analysis of a multi-institutional European dataset; who can get focused radiosurgery. Up to 10 brain mets have been treated without WBRT was without detriment. There was discussion of a graded prognostic assessment for various tumor types with brain metastases. There was additional discussion on Caris opportunities, the Fox Chase Cancer Center ONC201 trial that allows enrollment of brain tumor patients. There was discussion of a seminar on 12-9-15 at Fox Chase on CNS lymphoma where at NCI they are using combination temozolomide, dexamethasone, rituxan, ibrutinib among other agents.

3-10-15

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 presentations by individuals or sub-groups. 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... Expand

Drs. Jesty Abraham, Kamel Khalili, Alana O’Reilly, Denise Connolly were suggested to be invited to participate. The participants of the meeting introduced themselves and spoke about their translational research interests. Dr. Glenn Rall mentioned work by Dr. Zeng-Jie Yang who works on formation of medullobastoma and hedgehog signaling. He has high profile papers. He is a member of the CB program at FCCC. It would be good to be connected with the clinicians and other basic scientists. Dr. Rall’s interest is in the area of inflammation and infiltration of tumors. Coordinates inflammation group. He mentioned that Drs. Sid Balachandran and Zeng-Jie Yang have discussed working on inflammation in pediatric cancer. There was discussion about pathways such as PTEN, inflammation, gene therapy, radiation. There is opportunity for harnessing immunotherapy. Dr. Stephanie Weiss from radiation oncology mentioned the Microtron and relationships to PDT. The microtron is a linear accelerator that has extremely high energy that would potentially give better cell kill per dose but in reality it penetrates deeper. The high energy activates compounds deep in tissue while the dose is almost negligible in terms of radiation. It is radiodynamic therapy and represents an opportunity at FCCC. FCCC plans on doing phase I protocols initially and brain is a good site for this modality. With low dose normal tissue risk for toxicity is negligible with specific yet to be defined doses. There was discussion about how the Microtron will be featured, and what we will say we are doing with it that is innovative. There are opportunities to learn about the biology. Discussed opportunities to look for remote (abscopal effects), how cells die, various pathways that are activated including p53, NFkB, Akt and mechanisms of resistance. Dr. Weiss mentioned frequent rates of leptomeningeal disease that she has been seeing in her practice and she has the sense that rates may be higher in the region but this needs to be looked into. There was discussion of work done by Dr. Joan Massague at MSKCC on genes that promote metastatic spread to specific sites and looking in primary tumors and brain metastases for such markers and to consider potential therapeutic targets. There was mention that Dr. Jesty Abraham does neuroradiology and would be good to bring into this group. There was discussion about which investigators at FCCC work on stem cells in brain tumors as this is an area of opportunity. Dr. Alana O’Reilly works on stem cells and Dr. Denise Connolly also works on CSCs. There was mention that Dr. Kamel Khalili’s group thinks about CNS tumors in the neurovirology group at Temple and that inviting this group could enhance discussions and promote collaborations within Temple University. There was mention of oncolytic poliovirus virus to treat GBM at Duke. Measles virus is also used to treat myeloma at other centers. Measles infects and kills the tumor cells in conjunction of other therapies. The immune response in the brain is a ripe area for investigation. Dr. Weiss mentioned protocols she is working with Dr. Yanis Boumber including a Novo-cure alternating electric field therapy. Trials in recurrent gliomas showed the alternating fields give a PFS benefit without side effects. Expanding to look at other sites and diseases including brain metastases from SCLC. Some studies on primary tumors as well are planned. There was discussion of AG120 and IDH mutations as important in driving grade II and III gliomas, secondary GBMs. Agios has a drug AG120 in testing for recurrent gliomas. IDH1 is favorable in leukemia and gliomas and so can we use as a predictor for therapy and supercedes 1p19q and MGMT. MGMT, if methylated, shuts down the gene and that favors sensitivity to temozolomide. Dr. Weiss mentioned that Stu and Hagy showed in tumors with MGMT methylation patients did better with RT + Temozolomide. Not used in clinical practice as all patients end up receiving temozolomide and responses are seen with combined modality therapy even if MGMT not methylated. There is a question for elderly GBM patients and whether if when MGMT is methylated if RT can be with-held due to prediction of response to temozolomide. There was discussion about trainees and the potential for them to benefit from participation in this TRDG. There was discussion about how many tissues are in the biorepository. Dr. Weiss mentioned she identified 40 cases that have had brain metastases from GI tumors. May be these tumors go to the brain due to Her2 expression and she is pursuing this. Dr. El-Deiry mentioned lapatinib and its CNS penetration as well as off-target effect that activate death receptor signaling. Dr. Weiss mentioned intrathecal Herceptin is being used at some centers for brain metastases with Her2 overexpression. EGFRvIII has not panned out as a therapeutic target. Dr. El-Deiry mentioned opportunities with CSF tumor cell analysis. Dr. Weiss developed a tumor board and reaches out to neurosurgery as needed. Collapse

Fox Chase Cancer Center - Philadelphia, PA