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Melanoma and Skin 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.

12-6-16

Dr. Tony Olszanski spoke about “Melanoma/Skin Cancer Clinical Trials at Fox Chase Cancer Center.” The clinical portfolio was discussed to share current activities and relationships with industry. There is some effort on merkle cell tumors and data with immune checkpoint therapies. He spoke about melanoma specific trials and other open trials that may apply to melanoma (numerous trials in the phase I portfolio). Several target RAF although combinations with chemo has been difficult. Others include IFN plus pembrolizumab, anti-VISTA (currently on hold), OX40 agonist plus nivolumab or ipilumumab, anti-TIGIT, ICOS agonist, SYK inhibitor plus immunotherapy, anti-CSF1 (targeting stroma) plus pembrolizumab, anti-CCR4 (used to treat cutaneous T cell lymphomas in Japan) plus nivolumab (or tremelumumab that targets CTLA4), IDO inhibitor plus pembrolizumab, anti-TIM3, MEK plus anti-PD-L1. He mentioned how MEK inhibit plus RAF inhibitor are actually associated with fewer undesirable side effects including fever and squamous cancer. There was discussion that there would be opportunity to test novel agents despite all the immunotherapy trials. There was discussion about BET inhibitors and how they may be incorporated in trials. Dr. Olszanski mentioned that combination immunotherapy shows better outcomes albeit with higher risk of side effects. He spoke about Dr. Zibelman’s trial. Dr. Olszanski sees about 50 patients with metastatic melanoma each year and the surgeons see ~120 patients a year. He spoke further about the TIGIT trial (T cell immunoreceptor with Ig and ITIM domains) ultimately targeting T-reg cells. Dr. Olszanski further described melanoma specific protocols at FCCC. IRB 1082 Durvolumab (PD-L1) or Tremelimumab (CTLA4) plus IMCgp100 (bi-specific T cell receptor technology).  HLA-A2 is not melanoma specific. IRB 16-108 involves TAK580 (pan-RAF) plus nivolumab, nivolumab plus anti-CCR2 in second arm, or nivolumab plus ipilumumab plus vedolizumab (anti-integrin to treat associated colitis). IRB 14-032 involves “oncolytic vaccine” talimogene laherparepvec (TVEC) injected into the melanoma plus pembrolizumab; stage IIIB-IV unresected first-line trial. Melanoma specific and stimulates immune response.  IRB 15-2008 (ECOG) HD IFN or HD ipilumumab versus pembrolizumab for stage IIIA-IV fully resected disease. Results described at ESMO showing improved DFS and OS. There was further discussion of the effect of dose of anti-CTLA4 ipilumumab in metastatic melanoma. Dr. Olszanski spoke about sequencing trials (immunotherapy and BRAF/MEK inhibitors) in patients. There is less time for BRAF plus MEK to work when given later due to aggressive disease. There was discussion of some open questions such as predicting which patients with earlier stage disease who are likely to recur. There are panels of genes that are being looked at in melanoma. There is a need to develop less toxic therapies due to immune effects, develop “better” combination therapies, understand drug resistance mechanisms and evaluate duration of therapy.

9-21-16

Dr. Carolyn Heckman, PhD spoke about “Psychosocial and Behavioral Science Methods in Skin Cancer Research.” Dr. Zaidi has an R01 and DOD grant in melanoma. Drs. Testa and Zaidi have a pending grant. Dr. Heckman spoke about potential collaboration with psychosocial researchers, prevention and screening research. Her focus is on T3 and T4 translational research. Tanning, tanning addiction, skin cancer prevention. Implementation of prevention strategies and the effectiveness thereof. Moving interventions to the population, and use of social media. Her research involves questionnaires; online data collection. She spoke about risk behaviors for skin cancer including indoor tanning. Smoking and drinking are associated with risk behaviors. There is a 1.16 odds ratio of melanoma from 1 indoor tanning session. 1.34 after 10 sessions. There is also increased risk of non-melanoma skin cancer. The earlier the exposure the higher the risk. Indoor tanning is ~5 billion dollar industry annually. ~6% of population of US does indoor tanning... Expand

5-18-16

Dr. El-Deiry mentioned PAR-16-176 for R21 applications focused on exploratory translational studies. He spoke about clinical and research collaboration opportunities with Guardant with ctDNA. Dr. Jon Chernoff spoke about “The RAC1 Pathway as a Target for Melanoma Therapy”. Dr. Chernoff introduced genes mutated in melanoma including the RAS family (NRAS overrepresented in melanoma), BRAF, MAPK. Loss of NF1, KIT, cyclin D amplification. Linda Chin paper. He spoke about RAC1 P29S in melanoma ~5%, associated with UVB, often accompanied with NRAS or BRAF, associated with enhanced PD-L1 expression. He showed the spectrum of RAC1 mutations in melanoma. Rac interacts with PREX at the cell membrane. Rac signals to Pak and p110-beta each of which could be a therapeutic target... Expand

3-10-16

It was mentioned that the “Don’t Fry Day” campaign to prevent skin cancer takes place on the Friday before memorial day. Dr. Sujana Movva spoke about Castle data. Molecular analysis company that developed a test for uveal melanoma. There was discussion of uveal melanoma including discussion of BAP1 (Dr. Testa), discussion of NK cell injection into the liver (Dr. Sato at Jefferson). Dr. Movva has been working with Castle to develop a molecular signature, risk of metastatic disease. Her study involves FFPE specimens from 6 institutions including stage I-IV melanoma with outcomes at 5 years. There are 107 patients, 25 with local or metastatic disease separated into class I and II. There is a 28 gene signature that is being applied. 64 of 82 non-metastatic class I; added additional samples to 268. She described the patient characteristics. She described a training set where 67 of 164 patients developed metastatic disease. 88 were class I 5yr DFS 91% and 76 class II with much lower 5 yr DFS. The work was published in Clinical Cancer Research 2015: 21:175-183... Expand

11-11-15

Dr. El-Deiry spoke about the assay development RFA. Dr. Jeffrey Farma spoke about molecular profiling in melanoma using the 50 gene Cancercode for high risk, recurrent or stage IV melanoma. He mentioned 60 patient samples analyzing 101 mutations in 25 genes. The median age was 71. There were 2 or more mutations in 43%; 13% had no mutations and almost 90 % of BRAF were in codon 600. BRAF, Kit, NRAS were found as potentially actionable in 68% of patients. It is unknown if those without mutations are more aggressive. Acral were enriched. GNAS and HNF1A were newly identified. Are NRAS and BRAF mutually exclusive? Now has 93 patients including 44 who had recurrence and a recent abstract 157 mutations affecting 34 unique genes. Looked at DFS vs number of mutations and found correlations for >2 and <2 vs survival. There was discussion on CDKN2A mutations and family history; question about whether the mutations are in p16 or ARF. There was discussion on cfDNA, resistance. There was mention of mutant BRAF protein detection in serum from melanoma versus individuals with moles. There is a prognostic test for melanoma recurrence: 31 gene panel Melanoma-Dx test that may predict risk for recurrence at 5 years.

7-9-15

Dr. El-Deiry spoke about the recent FCCC Translational RFA on exceptional responders. He also spoke about the Precision Medicine Steering Committee. There was discussion about CancerCode being applied to 75-80 melanoma samples, and a similar # who had BRAF testing. Clinical and pathological data has been collected. There was mention of the EPCRS opportunity to support translational therapeutic or device studies. Dr. Harvey Hensley spoke about the Small Animal Imaging component of the institutional biological imaging facility. Described 7 Tesla retrofitted MRI system, Xenogen IVIS Spectrum Bioluminescence and Fluorescence Imaging, FMT, PET/CT as of May 2015 that is operational currently in the Young Pavilion and an endoscopy/colonoscopy capability for mice. Has animal housing facility for 500 mice in the Reimann Building. MRI dozen mice an hour. Bee Mintz does some work on melanoma imaging. He showed examples of detection of a colonic polyp by MRI (Dr. Clapper). Dr. Golemis has been imaging kidney cysts in Nedd9 crossed with other strains. He showed imaging lung tumors by several labs using the KRAS/p53 transgenic (Drs. Clapper, Golemis, Borghaei). He showed experiment by Dr. Denise Connolly with disseminating ovarian cancer cells intraperitonealy and dependence on VEGF. He showed luciferase imaging of TCF-reporter mouse made by Dr. Clapper in the background of the FCCC APC Min/+ mice. He showed the use of an activatable probe (MMPSense 680) and described colon tumor progression model and MMP-7 upregulation as well as other MMPs. He showed endoscopic detection of MMPSense probe(+) colonic tumors. Dr. Hensley showed fluorescence tomography with the FMT2500 with a near-infrared probe. He described imaging of MIS-Tag mouse model of epithelial ovarian cancer developed by Dr. Denise Connolly. Between 1955 and 1963 90% of children in US inoculated with SV40-contaminated polio vaccines. He showed FMT/MRI capability with MISIIR-Tag mice. He described Cherenkov imaging by Matt Robinson 64Cu-PSMA imaging and showed fluorescent FDG imaging with 2-DG. He showed the Sofie G8 PET/CT capability and showed lung images for tumor imaging. There was discussion about precision medicine that is biopsy-based versus imaging based or the use of imaging to direct biopsies. There was some discussion of radiodynamic therapy with 5-ALA. Dr. Erica Golemis is working on putting an animal model together for imaging ALA.

5-14-15

Dr. Raza Zaidi spoke about novel biomarkers in melanoma. He worked with Dr. Glen Merlino at NCI developing mouse models and has been at Temple since 2012. He is interested in UV-induced melanoma, impact on melanocyte biology, and interested in non-mutational mechanisms of melanoma. 80% of nevi have BRAF V600E and 60% of melanomas. UV leaves a specific mark that is different from the V600E. How does BRAF mutation arise if unrelated to UV. What do other effects of UV aside from mutations contribute to melanoma. Dr. Zaidi generated a mouse model with melanocyte-specific GFP. The neural crest has melanoblasts, some GFP expression in eye and telencephalon. The bulge region has melanocyte stem cells. The transgenic mouse allowed isolation of a pure population of melanocytes for culture and so he can study effects of UV-A or UV-B (more melanoma-genic). Tested effects at 1 or 6 days after UV. Keratinocytes are very different from melanocytes. Most changes seen after UV-B at day 2 and day 7. UV-B induced a delayed interferon-gamma response signature... Expand

3-24-15

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 in depth presentations by individuals or collaborators. Coffee and cookies were available. This meeting is scheduled for every two months. 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 invite clinical or lab trainees to this meeting (let Rose Walsh know who you’d like to include).  A number of names were mentioned of colleagues who may be interested in participating and/or contributing to the discussion and collaborations. These include Dr. Carolyn Heckman who does research on screening and sun exposure and wrote a book “Shedding Light on Indoor Tanning”, Dr. Raza Zaidi at Temple for relevant work on interferon response, Dr. Igor Astsaturov for involvement in creating PDXs in melanoma, Dr. Joe Testa with interest in genetics, Dr. Kerry Campbell who is collaborating on tumor analysis for immune markers, Dr. Misha Mutizwa from Dermatology... Expand

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