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- Head and Neck TRDG: Meetings and Minutes
Head and Neck 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.
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11-11-16
Dr. Jeffrey Liu spoke about “Examining DNA Damage Response Genes in Head and Neck Cancer Racial Disparity”. Dr. Liu has been a Temple faculty member since 2011; he is a surgeon who operates 50% at FCCC and 50% at Temple. He previously trained at Cornell and Columbia, MSKCC. He is a collaborator with Drs. Camille Ragin and Erica Golemis. Dr. Liu spoke about squamous cancers within the organs in the head and neck region with focus on racial disparities. He presented SEER data from 1975-2013; incidence of H&N higher in blacks and mortality is higher as well. The curves are trending downward with decreased smoking. HPV cases have been on the rise since 2000 which is more common in whites where the rise in incidence is demonstrated. The drivers in the SEER data are smoking and drinking alcohol. African American and poor patients have a dramatically worse prognosis in H&N cancer and access to care is a major issue that matters. There was a higher frequency of advanced disease in African Americans even after controlling for access to care, smoking exposure and socioeconomic status. There is therefore a question as to whether there are biological factors that explain the racial disparities. Dr. Liu has been interested in DNA damage response genes and germ-line genetic factors. He has pursued a hypothesis that inherited differences in genes affecting tobacco metabolism and DNA repair pathways contribute to risk and prognosis in SCCHN. There was discussion about degree of inhaling smoke and menthol as possible but unproven factors. Dr. Liu spoke about translational directions funded by a grant looking at DDR genes, SNPs enriched in African American (AA) populations, sequenom-MassArray panel testing in Philadelphia AA set (control population), and are AIMs (Ancestral Informative Markers) enriched in any AA SCC patients. The study had a bioinformatics component in silico followed by sequencing. Found 196 AIMs in 33 genes from ENCODE data analysis. There is little data on non-white populations in TCGA. There was discussion about announcements of nivolumab approval in metastatic H&N cancer. It was mentioned that very few H&N cancer patients enrolled in the NCI MATCH trial had actionable mutations. Dr. Liu spoke in more detail about specific DNA damage repair genes and markers. There was some discussion that there is no information about epigenetic factors or gene expression.
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9-7-16
Dr. Oneida Arosarena spoke about “Osteoactivin promotes migration and invasion of head and neck cancer cells”. She trained at U. Michigan and SUNY Syracuse and is working on bone cell biology and does some work in collaboration with Dr. Fayez Safadi. She is interested in osteoactivin. Oral Squamous Cell Cancers (OSCC) represent 40% of Head and Neck cancer and the 5 year survival is 50%. Bone invasion is an independent risk factor for poor prognosis. Invasive tumors more common in minority populations and Dr. Arosarena is interested in why that is. OSCC bone invasion is osteoclast-mediated (as opposed to hematogenous spread) and involves osteoclast activation factors. RANKL is induced by PTH, TNF, IL6, IL-1, IL-11. OPG competes with RANK to suppress metastases. RANKL is induced on osteoblasts which binds to RANK on osteoblasts. Dr. Arosarena has examined archived tissues looking for regulation of RANKL by TGF-beta in OSCC samples. She recently published results (https://www.ncbi.nlm.nih.gov/pubmed/26636434). There was discussion of translational research directions including effects of bisphosphonates and potential experiments in mouse models of bone invasion, and further studies of osteoactivin in clinical samples. There was mention of an osteoactivin antibody therapeutic in phase III in melanoma.
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4-28-16
Dr. El-Deiry mentioned an R21 RFA on clinical and translational exploratory/developmental studies. http://grants.nih.gov/grants/guide/pa-files/PAR-16-176.html Dr. Miriam Lango mentioned that there are many patients being seen with larynx cancer at Fox Chase Cancer Center. There was discussion about the need to follow-up with Caris on a submitted LOI and mention of Syapse meeting occurring tomorrow to explore a data aggregation platform for precision medicine studies. Dr. El-Deiry spoke about various opportunities of liquid biopsies. Dr. Thomas Galloway spoke about “TTI and Head and Neck Cancer”. He described a case where delay in diagnosis was significant in a patient with hypopharynx cancer with symptoms. The delay took 6.5 months (192 days). Then the patient came to FCCC and it took 24 days prior to beginning therapy. He mentioned that nationally, treatment delays are being seen regardless of stage or how patients are being treated and these have gotten worse over the last 15 years. Transitions of care are a big driver of delay in therapy. He showed some poor prognostic factors in terms of hazard rations including racial and socioeconomic factors. Patient outcomes correlated with how quickly tumors are growing in oropharynx cancer. There is already some risk stratification into low, intermediate and high risk (RTOG 0129 risk groups). There was discussion about whether Ki67 or other histopathologic parameters correlate with the risk groups. At this time this is not standard practice in head and neck cancer. There was discussion of imaging modalities including 18F-MISO and FLT. The TH4000 study is opening at FCCC; an EGFR inhibitor that is reduced under hypoxic conditions and converted to an active form that has better tumor penetration. The trial is in Head & Neck cancer and uses HX4 for hypoxia imaging. There was discussion about morphologic profiles of HPV-related Head & Neck cancer that have less projections and are more clearly demarcated by imaging. Typically positive margins are dealt with by post-op therapy such as RT, not by intraoperative cautery that may affect tongue function. There was discussion about management of lymph nodes. High risk tumors grow more quickly. Ki67 is low hanging fruit for risk stratification. Bcl2 is routine at MGH per Dr. Bauman. There was discussion about lymphocytic infiltration and PD1 in the context of clinical protocols. There is a Head & Neck cancer month in April and increasing awareness of different forms including those not related to smoking.
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2-10-16
Dr. Camille Ragin spoke about genomic risk association studies, genetic ancestry contributions to Head & Neck cancer risk and outcomes. She is interested in Phase I enzymes, phase II enzymes, and DNA repair pathways. SNPs, tobacco metabolites; work supported through an American Cancer Society research grant. Now she has added DNA repair pathways and is interested in validating bioinformatics and SNPs associated with risk of head and neck cancer. She has enrolled 100 cases and 775 controls in the catchment area and collected saliva and urine and is working with the PA State registry in addition to TU-FCCC patients. She is not focusing primarily on smokers. There are 229 tobacco metabolism genes and 33 DNA repair genes; some more polymorphic than others. She has compared SNP allele frequencies between whites and blacks and then did functional analysis. For SNPs in coding sequences did functional modeling and for non-coding sequences, she used TCGA to look at impact on gene expression. Dr. Ragin discussed specific genes, their function, and the potential impact of polymorphisms. She also discussed non-coding SNPs as well as potentially remote effects of SNPs on DNA repair gene expression. She mentioned there are no GWAS studies involving African Americans. There was discussion that the associations that are being uncovered may not only be with disease risk but also treatment response. She gave some possible examples and described some plans for laboratory studies. One goal is to eventually be able to look at multiple SNPs in combination that impact risk of Head & Neck cancer as well as survival differences between blacks and whites. The impact can be part of risk assessment for smokers in the future. Findings may also apply to lung cancer.
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12-9-15
Dr. Suraj Peri spoke about TCGA analysis in SCCHN. These tumors are heterogeneous, and important to compare HPV+ vs HPV-. He reviewed a 2004 study by Christine Chung in Cancer Cell where the study looked at 60 tumors found 4 sub-types: Group 1: basal (HIF genes upreg; neuregulin), Group 2: mesenchymal (vimentin, cadherin), Group 3: atypical (keratin 1, keratin 9; mostly HPV+), Group 4: classical (xenobiotic pathways; smokers). He reviewed a Clinical Cancer Res 2015 paper 21:870-881 that involved discovery and validation cohorts; transcriptomic data and reported basal, classical, immunoinflammatory subtype but did not describe an atypical category. The atypical (HPV+) fell into classical and mesenchymal but not the basal category.
Survival curves based on category; HPV+ had better prognosis. Dr. Peri spoke further about TCGA data: currently 528 tumors; 279 published. 172 oral cavity, 33 oropharynx, 72 laryngeal
majority male heavy smokers. RNA-seq if >1000 mapped RNA reads for E6 and E7 these are called HPV+ in addition to p16 reads. He spoke about a 2015 Nature paper 517:576-582 that described a comprehensive genomic characterization of head and neck cancer (http://www.nature.com/nature/journal/v517/n7536/full/nature14129.html). He spoke about EGFR amplification, caspase 8 mutation, p53 mutation, p16 mutation, Notch 1, HRAS mutation tracked with stable copy number and casp 8 mutation. He mentioned that Walter et al from UNC published 138 HNSCC cases from UNC and conformed to the Chung classification. He described methylation data and mentioned a 2013 PNAS paper that included some MSI cases. He described results from Peri et al., submitted manuscript looking at TCGA data for 256 cases for which all 4 molecular datasets are available. There are a number of future directions in terms of prognostication, and therapeutic development.
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9-23-15She spoke about a Korean study of 191 newly diagnosed HN cancer patients; used MDADI assessment and video swallow findings. Patient reported outcomes predict survival providing information that is not captured by any swallow test. Is it the work of maintaining nutrition or cancer-related weight loss? A Canadian study of 635 patients previously untreated HN cancer patients used the PG-SGA tool and found an aggregate of symptoms predicted reduced intake, weight loss and survival. Could symptom burden reflect underlying cachexia. A bunch of serum factors including various cytokines such as IL6 are associated with cachexia syndrome. The TWEEK-Fn14 pathway regulates skeletal muscle mass and metabolism in response to injury; TNF family and Fn14 is receptor that is overexpressed in many tumors. Amilia Johnston et al, Cell, 2015. http://www.cell.com/cell/abstract/S0092-8674(15)01045-4 Anti-Fn14 in a mouse model blocks cachexia signal. There was mention of a gorelin agonist in lung cancer. How does receptor signaling by Fn14 cause weight loss? It likely involves downstream cytokine stimulation. Things get even worse with treatment. There was discussion of whether blood samples were saved and whether it may be useful to go back and look for specific candidate cytokines. Discussion of screening for expression of Fn14 in tumors, looking at the signaling; Is it overexpressed in cell lines; can it be blocked by some FDA-approved drug or blocking antibody? What company is trying to develop this? The Cell paper wasn’t exclusively focused on Head & Neck cancer and included other tumor types as well. There was discussion about whether HPV(+) versus negative might be different in the cachexia, and whether this is all a function of what is elaborated by the tumors. Discussion about whether nutrition might prolong survival. Might it be possible to develop a proposal around measurements suggested by this discussion in the context of a therapeutic trial in head and neck cancer. The EPCRS mechanism and other mechanisms for pilot support may be applicable. Dr. Ranee Mehra provided an update of translational directions with particular focus on a project involving genome analysis (Ambry collaboration), HNC TMA that includes PD1, PDL1. The OncoScan assay showed FAM84B is significant. Also looked at p16, myc amplification. There was interest in smoking, HPV and HIF1alpha. OncoScan looks at amplifications. Identified FAM84B amplified at 8q24. Involved in various tumors including breast, prostate, colon. FAM84B is close to myc and so they are frequently co-amplified. No association between amplification of FAM84B and p16 status or smoking. FAM84B is related to DNA repair in breast, colon, prostate cancer. About half the cases had amplification but not obviously associated with outcomes. Discussion regarding whether there may be an association with cisplatin resistance, p53 mutations. Is it general genomic instability? Are the proteins overexpressed? Question of whether this could be detected in serum. FAM84B was recently described in esophageal cancer where they measured levels in CTCs, mentioned its knockdown reduces tumor growth and some drugs were mentioned as associated with its reduced expression such as HSP90 inhibitors or MEK inhibitors (Hsu et al., Scientific Reports, May, 2015). There may be opportunities here to look at effects of ganetespib, and to explore its use as a biomarker in Head & Neck cancer given this recent progress. Collapse
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4-15-15They included TCGA analysis of various parameters and survival. A second project has been looking at EGFR, Her2, PTEN and NSDHL as biomarkers in HPV(-) Head & Neck cancer. This is at a preliminary phase. Dr. Mehra mentioned the CDK4 inhibitor. There was discussion about CDK4 inhibitor combinations with chemotherapy or other targeted therapy such as EGFR-directed therapy. There was discussion of the use of immune checkpoint therapy as a strategy to treat HNSCC both HPV(+) and HPV(-). Pembrolizumab has shown responses in both HPV+ and (-). Novulumab data is forthcoming. Pembrolizumab plus radiation is in planning for a collaborative trial with UNC and U. Chicago. More has to be learned about markers of response. Nanostring was done at U. Chicago. There was discussion regarding the possibility of CTC analysis with the pT356 Rb antibody. Novartis and Lilly have drugs for a window of opportunity trial with pre and post treatment biopsies. Dr. Camille Ragin spoke about epidemiology work regarding gender disparities in HNSCC. Black men have a higher incidence of tonsil cancer and a higher mortality, and larynx cancer also has higher rates in black versus white individuals. She is looking at possible factors including HPV, tobacco as well as mutational landscapes to account for differences. HPV(+) rates are lower in blacks with HNSCC. Saw a similarly low rate of HPV(+) in Asians. She started asking the question why HPV(+) is so high in whites with HNSCC. She found that blacks are more of an intermediate group that are HPV(+)p16(-) with disease that has a poorer prognosis. Dr. Ragin described a genomics project at FCCC-Temple supported by the ACS. She is making associations with SNPs in the black population and survival as well as tobacco metabolites. She has identified ~47K African derived SNPs and has just started recruiting cases and controls within the catchment area. Dr. Ragin is also pursuing genes regulating DNA repair and tobacco metabolism as prognostic factors in HNSCC. She is analyzing 172 genes in the DNA repair pathway using African derived SNPs. She spoke about mutational landscape of laryngeal cancer by race. Collapse
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1-29-15Her research has involved using TMAs and IHC looking at ERCC1 and trying to develop a clinical assay for platinum resistance and she is adding other markers to make correlations with outcomes. She has been collaborating with Erica Golemis and with Biostatisticians looking at phospho-Rb, p16, p53, p-Akt and other markers. She has been working with a set of 5 TMA’s with 109 well-annotated cases of head and neck cancer. Some antibodies didn’t validate. Most cases are HPV(-) oral cavity and laryngeal tumors from a surgical series. There is a second TMA that Drs. Galloway and Fleeter annotated for p16, about 50% HPV(+). There is interest in HIF1-alpha and outcomes and smoking status. There is more interested in genomics moving forward. Cases have been sent to Ambry as part of assay development and they have initial results. Others have done genomics with mutations, less on amplifications, or methylation. Dr. Drew Ridge who is Chief of head and neck surgery spoke about the increasing incidence rate of HPV(+) head and neck tumors (10K per year) with decreasing smoking (but still 50K HPV(-) per year). Dr. Camille Regan is a molecular cancer epidemiologist looking at racial variations in Head & Neck cancer. She is looking at outcomes in African American patients. She checked a series of 45 oropharyngeal cancers in African Americans that were tested for HPV and p16. The majority are HPV-16(+) and the p16 negative are consistent with tobacco as a driver. She has received recent ACS funding for 5 years to look at tobacco related cancer in HPV(-) head and neck cancer looking at tobacco metabolic pathways in African Americans as far as risk and survival in vs. Caucasians. Another arm involves cases through the state cancer registry is already enrolling. She is looking at DNA repair pathways through translational pilot funding. She discussed the possibility that the mutational landscapes may be different as a result between the cases of head and neck cancer between African Americans and Caucasians. Dr. Matt Robinson characterized his research as disease agnostic. He focuses on antibody development vs. the ErbB family. He has an interest in Head & Neck cancer and Her3 as a resistance mechanism through upregulation and heterodimerization of family members. He is interested in imaging agents and therapeutic approaches to improve efficacy. He has worked with a bispecific antibody against her2-her3 that ended up at Merimack as MM111. The Ab is in clinical trials in breast and gastric cancer and showing promise in gastric in combination with Trastuzumab. He spoke of canonical and non-canonical pathways as targets. Interested in Ab-drug conjugates to improve therapeutic window and interested in EGFR and use of anti-Her3 in combination with cetuximab. Dr. Ridge primarily does clinical trials and has a background in structural biology. He serves as Head & Neck Committee chair at NCI, and has ECOG, ACRIN involvement. He spoke about the marketplace of ideas and the need for our investigators to use the disease name in grants as a critical mass is built. He spoke about strategic recruiting. Dr. Ridge mentioned that our successes at FCCC have been in patient accrual. Head & Neck cancer is a niche site and pointed out that the mechanisms of carcinogenesis are not going to be so different in Head & Neck cancer and lung cancer. Dr. Ranee Mehra mentioned there are 3 trials of immune checkpoint Rx; pembroluzumab was tested here in a cohort expansion. Roger Cohen has been developing a consortium of centers. It is recognized that Head & Neck cancer is an opportunity in immune therapy. Dr. Miriam Lango is a Head & Neck surgeon who years ago spent time with Dr. Sidransky in head and neck cancer research at Johns Hopkins. She is currently involved with ACRIN surgical and radiographic trials. She is interested in outcomes and swallowing and does health services research supported by a small grant. Dr. Mehra mentioned that a goal of the keystone program was to apply for programmatic grants and that annotation of TMAs came out of that. The ERCC1 project was supported through the Keystone Program. There was a goal to hire a translational scientist in Head & Neck cancer ~4 years ago. Dr. Ridge referred to previous P01 efforts. Dr. Robinson spoke of collaboration with Drs. Roland Dunbrack and Heinrich Roder who use computational modeling to enhance the stability of antibody therapeutics led to a transformative R01. Mentioned an R21 under review on Xray crystallography of Her3. Some Keystone funds were directed at crystallography. A biotech company called Rational Antibody Design emerged as a start-up. Dr. Mehra poke about thyroid cancer as there was historically interest at FCCC and we have participated in trials including Cabozatinib, and phase II with axitinib trials. She is opening a phase I trial for HRAS mutant thyroid cancer. Dr. El-Deiry mentioned the potential to develop quinacrine in combination with sorafenib as therapy for anaplastic thyroid cancer. Quinacrine has single agent anti-tumor efficacy that was demonstrated in his lab and his efforts thus far have led to combination of quinacrine plus capecitabine clinical trial that was opened at PSU and now in the process of opening at FCCC in metastatic colorectal cancer. Dr. El-Deiry holds the IND for this combination and this is process of transfer to FCCC. There is preclinical data for synergy between quinacrine and sorafenib and a direction to develop this for liver cancer and for thyroid cancer. There is in vivo data that the quinacrine plus sorafenib combination is well-tolerated in an orthotopic model of anaplastic thyroid cancer. Quinacrine appears to have multiple targets including NFkB, STAT3, Mcl-1, and it works in p53 deficient tumors and has an anti-angiogenic effect. There is opportunity to develop this combination in thyroid cancer. Drs. Ridge and Lango mentioned there is an increasing incidence of thyroid cancer and thus an opportunity at FCCC to develop efforts in this area. Dr. Ridge further elaborated on previous P01 efforts revolving around EGFR signaling as the focus in Head & Neck cancer. There was work on antibody-receptor interactions, work on the Aurora Kinase by Dr. Igor Astsaturov, Roder’s interaction with Igor on PDZ domain proteins and their interactions with EGFR. The following were suggested as future attendees of the meeting: Suraj Peri, Jeff Peterson, Tim Beck, Heinrick Roder, Niklas Finnberg. Collapse
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