Melanoma and Skin 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.

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
Higher among women and whites. 13% of high school students. Dr. Heckman studied 500 women by survey and phone interview. She found evidence for some addictive symptoms, anxiety and some information that tanning decreased negative feelings. The FDA recommends regular screening for indoor tanners. Screening is increasing but only 30%. Dr. Heckman spoke about tanning dependence. “Tanorexia” is a lay term. A comment was made that in Asia there are patterns in the other direction to have fair skin. UV exposed keratinocytes produce beta-endorphins. Orek and Bartek, Cell 2007. Naltrexone can reduce dependence and cause withdrawal symptoms. Dopamine and striatal area related to addiction. There is only minor genetic difference in people who are tanning dependent. Correlates with tanning: sun burning, smoking, lower skin protection, trouble paying for tanning. Dr. Heckman edited a book on indoor tanning in 2012. She spoke about interventions to modify cancer risk behaviors. She spoke about tailored internet intervention to help people visualize skin damage. 1234 participants nationally to take survey and randomized to intervention during the summer. She noted an issue of some individuals enrolling multiple times: reduced sample size to 965. UV exposure and sunburn decreased over time in the intervention group. The use of sun screen increased and indoor tanning decreased. Intervention module use correlated with observed effects. She is doing a follow-up study focused on dissemination and implementation (supported by an NIH R01 grant). She plans to recruit more broadly and use social media. Changing the intervention to increase engagement; mobile version, peer interaction. Will be looking at longer-term outcomes, costs and is using an online consent form. There was discussion about exercise as a potential intervention. Dr. Heckman is involved with Society of Behavioral Medicine for position statement published in a journal called Translational Behavioral Medicine. In PA, tanning is prohibited in those who are under 17 (some minors). Dr. Heckman mentioned “Don’t Fry Day” that has been going on for 8 years as a national campaign. Collapse
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
P29S mutant melanomas are resistant to various inhibitors including Vemurafenib, Dabrafenib, Trametinib or a MEK inhibitor. Dr. Chernoff spoke about “Next-gen” Pak inhibitors. He showed Rac1 P29S phenotypes in zebrafish in comparison with BRAF or KRAS mutant mRNA injections. He adds drugs to the water to inhibit signaling in the zebrafish. p-ERK disappears with a Pak or a MEK inhibitor. The inhibitors also block p-PAK in the zebrafish. There are however issues with adding inhibitors for extended time during zebrafish development but there is a window for reversing oncogene effects. Dr. Chernoff is collaborating with Dr. Meenhard Herlyn at the Wistar Institute to treat a panel of cell lines with BRAF or RAC1 -/+ NRAS mutations. He is using PAK inhibitors to show specificity to RAC1 mutants while with Vemurafenib the RAC1 lines were resistant. Dr. Chernoff is also looking at cell lines from Yale in collaboration with Dr. Ruth Halaban. His approach involves contrasting the PAK inhibitor with the RAF inhibitor. Dr. Chernoff spoke about melanoma models including a Zebrafish transgenic model: transgenic Kita:Gal4 with p53-/- and mitf-/- where he is looking at RAC1 expression in this background. He is also developing conditional knock-in RAC1 alleles in mice and working on a CRISPR-Cas9 knockin mice for genome editing and cancer modeling (Dr. Feng Zhang). Dr. Chernoff mentioned there is on target toxicity to the heart due to PAC2 with first generation inhibitors. Collapse
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
A validation set had 104 cases and similar results. PD-L1 not on the list. The 28 genes were assessed by RT-PCR so the focus was on mRNA expression. The assay performance was assessed and seemed better in predicting metastases by class II for stages >1. There is utility of sentinel node biopsy. The gene set does not supplant sentinel node biopsy. There was discussion about what to do with gene information as far as adjuvant therapy. There is need for prospective trial. The curves have a tail that may be of interest for the poor prognostic category and so there may be a difference between the patients who metastasize early or there may be a difference in response among the more aggressive tumors. There is a lot of clinical data at FCCC and discussion about directions. There is an interferon-controlled trial for stage III at FCCC. There was discussion about liquid biopsy and whether they can predict metastasis prior to scans. Guardant is doing tests and there is a melanoma CTC test. It may be worthwhile to look at blood samples from patients with stage II and III melanoma versus class I and class II gene expression profile and then if possible look at liquid biopsy pre-operatively as well as post-operatively to see of any measurement in blood might predict metastasis before CT scans. Some pilot data regarding feasibility could support an IIT, and fresh blood could be obtained using the opportunity blood collection protocol. BRAF mutation may be low hanging fruit but guardant is looking at many other genes. There was discussion about looking for cfDNA from patients with dysplastic moles. Collapse
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
UV-B induces an inflammatory microenvironment. Macrophages are recruited into the skin after UV-B. Isolated a melanoma cell line from mice and mixed with macrophages that have been activated by UV. Is IFN-gamma playing an active role? If anti-IFN-g injected this inhibited tumor growth. He showed that human melanoma-associated macrophages make IFN-gamma. Dr. Zaidi has been pursuing the hypothesis that IFN-gamma secreting melanoma associated macrophages can be used as prognostic biomarkers. UV irradiation induces influx of macrophages in the skin of normal human volunteers. Neutrophils are also recruited but they exit in adults. In neonatal mice the infiltration is only macrophages. Dr. Kerry Campbell brought up issue of lymphocytes in the adult mice may be counteracting the macrophages. Dr. Zaidi spoke about immune checkpoints. CTLA4 or PD-1 are T-cell brakes. CD28 is an activating receptor, along with OX40, GITR, CD137, CD27, and HVEM. CTLA4 is inhibitory along with PD-1. TIM-3, BTLA, VISTA and LAG3 are other inhibitory receptors. Ipilumumab has an 11% response rate; Nivolumab has a 32% response rate; Ipilumumab plus Nivolumab have a 61% response rate in metastatic melanoma. However, predicting response is the challenge. CTLA4 is the highest induced gene ~200-fold following UV-B irradiation in melanocytes. In collaboration with Dr. Jedd Wolchok at MSKCC Dr. Zaidi showed CTLA4 expression in human melanoma cells and tissues. He is interested in regulation of CTLA4 after UV-B and what is its function? Provided evidence that CTLA4 is induced by IFN-gamma treated melanocytes. PD-L1 is also induced. Question by Dr. Kerry Campbell about B7 ligand induction. IRF1 binds to CTLA4 promoter in an IFN-gamma dependent fashion. Dr. Zaidi did co-culture experiment to assess function of induced CTLA4 in UV-B irradiated melanoma cells. T-cells express B7. Showed hi CTLA4-expressors were protected. Keratinocytes do not make CTLA4 in response to IFN-gamma. Second hypothesis that CTLA4 expression on melanoma cells can be a predictive biomarker of response to ipilumumab. He is working with the biorepository to get tissues. Future directions include further testing of the hypotheses. Dr. Von Mehren raised a question about correlations between macrophages and TILs. Nevi are transformed but senescent and then deletion of PTEN or CDKN2A leads to tumor progression. There was discussion about tissue from surgery including lymph nodes and resected metastases. There was discussion about melanoma CTCs and circulating macrophages. There was discussion of combination of checkpoint inhibitor plus BRAF inhibitor. Dr. Zaidi is working on IFN-gamma inhibition for therapy as well as targeting the macrophages. Has HGF mice that produce sarcomas by 18 months and melanomas by 10-12 months after UV or faster if crossed with CDKN2A mice. Collapse
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
The participants of the meeting spoke about their translational research interests. Dr. Sujana Movva is a medical oncologist who sees melanoma patients and opens up clinical trials. Some fellows work with her to help review databases or molecular profiles. She also sees patients with sarcoma. Dr. Anthony Olszanski serves on the NCCN panel and lectures on melanoma. The patient population he sees currently is 50:50 between GI and melanoma. He mentioned that we are well-positioned in Philadelphia—with potential to grow. He mentioned that Jefferson’s melanoma program is headed by Dr. Mastrangelo and at U. Penn Dr. Lynn Schuchter leads the clinical effort and has done so for years. At CINJ Dr. Howard Kaufmann leads melanoma efforts and is interested in immunotherapy. The program at FCCC has opportunity. Dr. El-Deiry mentioned Dr. Meenhard Herlyn and the SPORE as well as P01 in melanoma at the Wistar Institute and a strong melanoma program at Penn State University. It wouldn’t be too difficult to build bridges should anyone from FCCC be interested. There was discussion that we need to assess where we are with databases, tissues in the biosample repository. It was mentioned that FCCC is getting a Nanostring machine in the near future and the capability of this technology to measure RNA expression from paraffin-embedded archival tissues. There was mention that Dr. Matt Zuk left and went to Florida; was doing dermatology, screening, and role not filled. Dr. Gil Yosipovich is Dermatology lead at Temple. Dr. Jeffrey Farma has worked to build referral base. Dr. Sanjay Reddy is doing 2-3 surgeries per week in melanoma. The clinical volume is here at FCCC and retention of patients is here due to availability of trials. Drs. Olszanski and Movva have opened all available ECOG trials. 1609 was the most interesting in looking at adjuvant interferon versus two doses of ipilumumab. This trial completed accrual by November 2014 and is expected to be an influential study. Another trial looking at ipilumumab plus interferon did not enroll and will close. FCCC also had an ipilumumab plus avastin study for advanced disease. Immune checkpoint including anti-PD1 has moved into first line therapy for metastatic melanoma. FCCC is opening an ipilumumab versus nivolumab (BMS) that is going to the IRB soon for stage III. Another study is TVEC pembrolizumab; plasmapheresis-based TIL therapy. Getting studies here has been challenging although there has been tremendous growth versus 4-5 years ago when there was only one trial in melanoma. There is currently interest in pan-RAF inhibitors. TEVA med is blocking BRAF and CRAF and EGFR. A study referred to as 14054 has 3 arms for metastatic disease in phase I and includes the pan-RAF inhibitor MLN2480 plus an mTOR inhibitor in the first arm (Dr. Olszanski mentioned experience with a patient on this arm who required hospitalization due to Steven Johnson Syndrome). The second arm involves the combination of Alisertib (aurora kinase inhibitor) plus MLN2480 and the 3^rd arm involves combination of pan-RAF inhibitor MLN2480 with paclitaxel. FCCC has not opened vemurafenib or dabrafenib trials in the adjuvant setting because of concerns they may make disease worse. With vemurafenib>dabrafenib keratoacanthomas/squamous cell cancers of the skin have been concerns and especially would increase risks in the adjuvant setting. Drs. Olszanski and Farma have worked with Dr. Kerry Campbell doing flow cytometry. They have been looking at primary tumors or lymph node metastases for signatures looking at immune markers. They have data on 10 patients. Age of patients was older and there is some issue about a control group. It was suggested to ask Kerry to come and speak about the data, in terms of where it stands and what are next steps. It was mentioned that the vast majority of tumor tissue samples in the biosample repository are from stage I, II, and III patients and much less so from patients with stage IV disease. There is need to address this to capture more stage IV tissues for a variety of scientific questions. Dr. Farma mentioned that everyone with stage III, and IV has been getting a 50 gene test with abstracts submitted at SSO, ASCO, and other meetings describing the initial experience in 45 pts. Patients in this cohort have demographics and treatment data. Dr. Alfonso Bellacosa mentioned he is collaborating with 2 people who are doing NGS; Nick Hayword at Royal Brisbane Hospital, and another person in Tuscany. He mentioned they are willing to share data and to look at specific genes in their data. He also mentioned the Ca bioportal at MSKCC collaboration plus other data. Drs. Farma and Movva mentioned a Melanoma Dx test through a company (Castle Bioscience). The company wants tissue, interested in having FCCC sign up for a registry. Dr. El-Deiry spoke about the kinome assay James Duncan technology that has been developed and potential applications in melanoma. There was a discussion about whether we should spend more time analyzing non-responders. Dr. Olszanski mentioned a patient who was a responder to ipilumumab and when disease relapsed it wouldn’t respond to pembrolizumab. The patient’s tumor was rechallenged with ipilumumab and didn’t respond. Dr. Movva spoke about interrogating signatures from responders and non-responders. There was discussion about newer technologies for serum DNA, and circulating tumor cells and scenarios where they may be used to monitor disease status as well as to analyze resistance mechanisms or prognostic markers. There was a general discussion about what can we do at FCCC that would be unique or develop a niche. Dr. Movva mentioned mucosal melanomas (it was mentioned that there is a strong focus on uveal melanomas at MSKCC)—do we have tissue, NRAS in cancer code? Dr. El-Deiry spoke about hyperspectral imaging technology available in his lab at FCCC. This uses hundreds of wavelengths to provide spectral signatures of preneoplastic or neoplastic lesions that can be followed over time and/or with therapy. He mentioned previous collaboration with Dr. Keith Flaherty years ago when Dr. Nadia Khan was a resident and they did imaging of melanoma patients when the plexicon compound that later became vemurafenib was being tested at U. Penn. The machine is now here at FCCC and available for clinical protocols as a low risk type of measurement that collects data on lesions in an unbiased manner (spectroscopy). There was additional discussion regarding potential opportunities with imaging sentinel lymph nodes using isotopic or fluorescence/near infrared dyes. Drs. Margie Clapper and Harvey Hensley were mentioned as potential collaborators and that there is also interest in intra-operative imaging of minimal residual disease particularly in the peritoneal cavity. Dr. Reddy mentioned that we see plenty of patients at FCCC with stage I and II melanoma. There was discussion that in some patients there are questions regarding management of lymph node disease. There may be opportunities with sub-ungal melanomas. Dr. El-Deiry spoke about potential directions to consider as far as the biology of the melanomas and intra-operative sampling of circulating tumor cells. Dr. Farma mentioned that some patients have Bulky stage III disease and Dr. Reddy mentioned that during surgery depending on the location of the tumor it may be feasible to sample the blood proximal or distal to a tumor. It would also be relatively easy to measure CTCs during tumor manipulation. Dr. von Mehren mentioned that it would be of interest to know the variability in CTC counts and that it would be of interest to look at disease recurrence/DFS and make correlations. Dr. El-Deiry mentioned it would be feasible to look at prognostic markers on CTCs and there is technology to do genomics on limiting numbers of cells including Nanostring. Dr. Bellacosa spoke about TDG in connection with genomic stability as an emzyme that demethylates the DNA. TDG protects cells from mutations and activates transcription through demethylation. He looked at melanoma. A mouse knockout of the TDG gene was lethal and this pointed to effects on neural crest. He mentioned that melanoma in general has low levels of TDG so what happens if you reduce levels of TDG? He mentioned that it is counterintuitive to reduce levels of a protective gene. He pursued this as an experimental strategy and thought he would see increased tumor phenotype with reducing TDG but actually observed that melanoma cells stopped growing. The melanoma cells with TDG knockdown started looking like melanocytes. He used a lentivirus vector to lower level of TDG through gene knockdown. Dr. Bellacosa performed high-throughput screening looking for TDG inhibitors, and has a few. Two of them recapitulate growth suppression on tumor cells including an anti-helminthic agent and another compound called Jaglone (black walnut extract). Nothing grows around black walnuts and it has been proposed as a chemoprotective agent. MITF is completely suppressed by Jaglone. He has submitted 2 patents to inhibit TDG for cancer therapy. He is doing a bigger high-throughput screen and making analogues in collaboration with the Moulder Center. He mentioned carboxycytosine is a biomarker that goes up and that Dr. Astsaturov has PDX’s in melanoma. There was some discussion about whether Jaglone itself or even black walnut extract might be translatable because there is always a balance in translational research between the feasible in the near future versus the desirable optimized lead or analogue that may take many more years to develop. There was some discussion of the desirability to get some in vivo data, and perhaps to use PDX models that use therapy resistant tumors from patients (i.e. resistance to BRAF inhibitors or immune checkpoint therapies). There was a brief discussion about vorinostat in melanoma and the issue of epigenetic priming to immune checkpoint therapy. There may be some interest within the group to explore further in terms of developing innovative translational trials. Collapse

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