bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B26: Combinational effect of sulforaphane (SFN) and epigenetic demethylation agent 5-aza-2’-deoxycytidine (DAC) on metastatic melanoma
Authors: Chiang Tung-chin , Su L. Joseph , Koss Brian S. , Washam Charity , Byrum Stephanie , Storey Aaron , Koss Alan J. 
Published: June 2022

Abstract
UV exposure-induced oxidative stress is implicated as the driving mechanism of melanoma development. Increased oxidative stress results in imbalanced reactive oxygen species (ROS) that damage DNA and dysregulated epigenetic modifications and leads to melanoma progression. Sulforaphane (SFN) is the natural bioactivated product of the cruciferous vegetable family (e.g., broccoli and Brussels sprouts) and is known to play a dual role in cytoprotection and to induce apoptosis in the tumor via antioxidant regulation and histone modification of epigenetic enzymes. We investigated the combinational effect of 5-aza-2’-deoxycytidine (DAC), an FDA-approved DNA-modification epigenetic drug and SFN in melanoma cells. We found further cell growth inhibition and an increased number of altered gene expression profiles, increased survival-related cytokine expression, as well as unique histones post-translational modifications (PTMs) upon combinational treatments compared to single treatment in vitro. These results set the stage for animal studies. The long-term goal of the current study is to find an optimal dietary dose of antioxidants from SFN to reduce the burden of oxidative stress, which may contribute to melanoma recurrence, a constant problem with current treatments. In addition to recurrence, a reduced dose of epigenetic drugs applied may minimize the side effects of single-high-dose treatment.
Citation Format: Tung-chin Chiang, L. Joseph Su, Brian S. Koss, Charity Washam, Stephanie Byrum, Aaron Storey, Alan J. Koss. Combinational effect of sulforaphane (SFN) and epigenetic demethylation agent 5-aza-2’-deoxycytidine (DAC) on metastatic melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B26.
Abstract IA01: Strategies for targeted and immune therapy in melanoma
Authors: Herlyn Meenhard 
Published: June 2022

Abstract
Melanoma cells activate pathways that are also activated in proliferating fibroblasts, endothelial cells, or even inflammatory and immune cells. The tumor-secreted proteins and expressed cell surface receptors are associated with growth, migration, invasion, and antiapoptosis. Then there is a group of molecules that is not associated with the phenotype of differentiated cells in skin or tumor stroma but that represents re-expressed developmental genes. Several developmental pathway genes, such as those associated with noncanonical Wnt or Notch signaling, are commonly found on stem cells from the dermis that can give rise to melanocytes and on melanoma cells, but they are absent from or not activated in epidermal melanocytes. We have recently identified a G protein-coupled receptor, LPAR1, that is highly activated in neural crest-like stem cells and melanoma cells and absent from melanocytes. Expression is associated with resistance to BRAFV600E inhibition. When other subpopulations of melanoma cells were characterized that were associated with resistance to BRAF, MEK, or ERK small-molecule inhibitors, their major common property was very slow proliferation, which was in contrast to the bulk of the tumor cells. These “label-retaining cells,” characterized by expression of the H3K4 demethylase JARID1B and the protease SERPIN E2, and the EGF and NGF receptors, are not only drug resistant but also highly invasive in vitro and in experimental animal model. Nonproliferating, drug-resistant malignant cells may pre-exist in tumors. As the majority of melanoma cells are killed by kinase inhibitors, multikinase receptor-expressing cells begin proliferating to repopulate the tumor to its original heterogeneity. Thus, melanomas contain small subpopulations representing only 0.1-5% of all malignant cells that are critical for growth, invasion, and therapy resistance. To achieve total elimination of all malignant cells, we have to develop strategies to target not only the bulk of the tumor cells but also those with intrinsic resistance to common drugs. To closely mimic the conditions in patients’ tumors, we have developed &gt;500 patient-derived xenografts. Together with the &gt;300 permanent cell lines, they represent all clinical, genetic, and biologic groups of the disease. Since the human tumors only proliferate in immune-deficient mice, we have developed two humanized models that recapitulate the infiltration by human leukocytes into the human tumors. Inhibition of checkpoints with clinical-grade inhibitors stimulated the immune response, leading to focal or general tumor regression; thus, the models allow investigating the mechanisms of both stimulation and suppression of the immune system.
Citation Format: Meenhard Herlyn. Strategies for targeted and immune therapy in melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA01.
Abstract IA06: Concepts of cancer and metastasis: Historical perspective
Authors: Lugassy Claire , Barnhill Raymond L 
Published: June 2022

Abstract
In medicine, as in all of human history, there is a permanent back and forth between two principal modes of thought: (i) magical/religious/ fears/obscurantism, leading to dogma;, and (ii) intellectual activities resulting in the questioning of dogma and opening doors to new concepts. Concerning cancer, since ancient Egypt, several methods of thinking have been instituted and then rejected, influenced by new discoveries but also by the cultural context. With respect to mechanisms of cancer metastasis, after considerable debate in the 19th century, intravascular dissemination of cancer was finally imposed and is still accepted as the only mechanism for distant metastasis. However, at present, other perspectives are now taken into consideration, and in particular melanoma angiotropism, pericytic mimicry, and extravascular migratory metastasis (EVMM). This new field of cancer research may open promising new strategies for reducing or preventing melanoma metastasis.
Citation Format: Claire Lugassy, Raymond L Barnhill. Concepts of cancer and metastasis: Historical perspective [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA06.
Abstract IA09: Tumor cell oxidative metabolism as a barrier to antitumor immunity in melanoma
Authors: Delgoffe Greg M. 
Published: June 2022

Abstract
The treatment of melanoma has been fundamentally changed by immunotherapies like blockade of coinhibitory “checkpoint” molecules like CTLA-4 and PD-1. However, despite these remarkable successes, even within T cell-inflamed, high-mutational-burden tumors, response rates remain low, likely due to additional immune inhibitory mechanisms present in the tumor microenvironment. It is now generally appreciated that the tumor microenvironment is characterized by a distinct metabolic landscape, having low oxygen tension, depleted levels of essential nutrients, and buildup of toxic byproducts. We sought to determine whether this metabolic landscape was variable from patient to patient and how this landscape affected antitumor immunity and thus response to immunotherapy. Using extracellular metabolic flux analysis, we profiled the metabolic derangement of patient-derived cell lines as well as direct ex vivo patient tumor samples, revealing striking heterogeneity not only in the degree of metabolic derangement but also in the type of metabolism a tumor cell was dependent on. Analysis of the tumor infiltrate revealed that a tumor’s preference for oxidative metabolism was associated with immune dysfunction, suggesting that the ability to generate hypoxic regions in vivo is a key aspect of immune resistance. We confirmed this finding in vivo using a novel model of melanoma in which individual metabolic pathways can be selectively targeted in a single-cell derived line: loss of oxidative metabolism in tumor cells sensitizes animals to PD-1 blockade immunotherapy, while loss of glycolytic metabolism has no appreciable effect on antitumor immunity. Analysis of melanoma patient biopsy samples prior to initiation of immunotherapy revealed that increased tumor oxidative metabolism and intratumoral hypoxia was associated with poorer responses to checkpoint blockade. Our data highlight the use of tumor microenvironment hypoxia as a potential predictor of immunotherapy resistance and shed light on the use of modulators of tumor cell oxidation as a means to improve responses to checkpoint blockade.
Citation Format: Greg M. Delgoffe. Tumor cell oxidative metabolism as a barrier to antitumor immunity in melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA09.
Abstract IA10: Targeting melanoma metabolism to overcome resistance to treatment
Authors: Betoff Allison , Zippin Jonathan , Merghoub Taha , Chapman Paul B. , Wolchok Jedd 
Published: June 2022

Abstract
Despite adequate oxygen levels, cancer cells undergo anaerobic glycolysis converting glucose to lactate (the Warburg effect). It is now thought that the advantage of this for the cancer cell is that it provides the carbon and nitrogen precursors critical for macromolecule synthesis (amino acids, nucleotides, fatty acids) while still providing an adequate supply of ATP needed for growth. Understanding this metabolic landscape may provide strategies to overcome mechanisms of resistance to therapy in melanoma. AMP-activated protein kinase (AMPK) has been shown to inactivate BRAF by phosphorylating Ser 729, and in preclinical models, this can be used to enhance inhibitors of BRAFV600E. In the high ATP environment of a melanoma cell, AMPK is typically low but inducers of AMPK, such as biguanides, increase AMPK. The biguanide metformin does not enter melanoma cells efficiently due to the lack of organic cation transporter (OCT) expression on melanoma cells. However, phenformin does not require OCT for uptake. We are conducting a phase I trial in BRAF V600E-mutated melanoma patients using dabrafenib/trametinib and escalating doses of phenformin. One of the pharmacodynamic effects of phenformin is weight loss, which we are measuring. Interestingly, obesity has been associated with improved outcome in male melanoma patients treated with anti-PD1 antibodies. In contrast, our data in melanoma patients treated with anti-PD1 antibody immunotherapy do not show an association between outcome and obesity. Another consequence of anaerobic glycolysis is generation and excretion of large amounts of lactate. There is evidence that lactate can inhibit T-cell function, and we will discuss strategies to block lactate transport to enhance immunotherapy.
Citation Format: Allison Betoff, Jonathan Zippin, Taha Merghoub, Paul B. Chapman, Jedd Wolchok. Targeting melanoma metabolism to overcome resistance to treatment [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA10.
Abstract IA13: Opportunities and challenges in melanoma early detection
Authors: Polsky David 
Published: June 2022

Abstract
It is well established that survival outcomes for melanoma are highest when these tumors are diagnosed and surgically removed at their earliest stages, prior to the escape of tumor cells to regional and distant anatomic sites. Screening efforts in other malignancies such as colorectal and cervical cancers have yielded benefits in reducing the incidence of invasive cancers and their respective mortalities. Therefore, early detection through broad-based skin cancer screening appears to be a logical step to reduce melanoma mortality. To date, this strategy has not been endorsed by the United States Preventative Services Task Force (USPSTF) due to a lack of conclusive evidence. For example, the initially promising reductions in melanoma mortality observed during a skin cancer screening program in Schleswig-Holstein, Germany, were not replicated in subsequent years in Schleswig-Holstein itself or throughout Germany when the screening program was extended countrywide. The lack of solid evidence demonstrating the benefits of skin screening on melanoma mortality, coupled with the potential harms of screening, and the phenotypic heterogeneity of melanoma raise important concerns regarding the utility of broad-based skin cancer screening programs. Nevertheless, melanoma’s visibility on the skin compared to internal malignancies, and the development of new diagnostic technologies, may help balance the benefits and harms of melanoma screening when considering the varied patient populations in which screening could be deployed. In this presentation we will review current data in the context of developing early-detection strategies to reduce melanoma mortality and/or the cost of care while minimizing potential harms.
Citation Format: David Polsky. Opportunities and challenges in melanoma early detection [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA13.
Abstract IA14: Immunosensitivity and resistance in advanced uveal melanoma
Authors: Carvajal Richard D. 
Published: June 2022

Abstract
Despite the ability to effectively achieve control of uveal melanoma at the site of origin, patient outcomes have remained suboptimal due to the ultimate development of recurrent distant disease in a significant proportion of those diagnosed, together with the limited efficacy of currently available therapies in this setting. Initial insights into the tumorigenic effects of the functionally activating, mutually exclusive, early event mutations in GNAQ, GNA11, PLCB4, and CYSLTR2 led to the development of a generation of trials evaluating the effects of inhibition of single or multiple downstream pathways including the MAPK and PI3K pathways. Given the dramatic efficacy of targeted therapy in cutaneous melanoma harboring a BRAF mutation, there was initial hope that a similar strategy might demonstrate comparable effects in uveal melanoma. Unfortunately, the completed and reported clinical trials targeting these pathways have demonstrated minimal, if any, efficacy. Likewise, despite the initial enthusiasm for immunologic checkpoint blockade for the treatment of metastatic uveal melanoma given the durable antitumor responses and cures achieved in cutaneous melanoma, the activity observed thus far has been limited. Nevertheless, with the critical and clinically significant advances made over that past 10 years in precision oncology and immuno-oncology, coupled with rapidly developing advances in our understanding of the biology of uveal melanoma, there is now a new cause for hope for our patients. Trials evaluating the inhibition of alternative nodes in activated pathways alone or in preclinically synergistic combinations are ongoing, new epigenetic strategies are being explored, and preliminary promising data from novel immunologic treatment strategies including adoptive cellular therapy and T-cell redirection all provide new optimism that these innovative treatment options may meaningfully impact the course of the disease.
Citation Format: Richard D. Carvajal. Immunosensitivity and resistance in advanced uveal melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA14.
Abstract PR01: A cancer cell program promotes T-cell exclusion and resistance to checkpoint blockade
Authors: Shah Parin , Cuoco Michael , Su Mei-Ju , Melms Johannes , Leeson Rachel , Kanodia Abhay , Mei Shaolin , Lin Jia-Ren , Wang Shu , Rabasha Bokang , Liu David , Shalek Alex K. , Tirosh Itay , Sorger Peter K. , Wucherpfennig Kai , Van Allen Eliezer M. , Schadendorf Dirk , Johnson Bruce E. , Rotem Asaf , Rozenblatt-Rosen Orit , Garraway Levi A. , Yoon Charles H. , Izar Benjamin , Regev Aviv , Jerby-Arnon Livnat 
Published: June 2022

Abstract
Immune checkpoint inhibitors (ICI) produce durable responses in some melanoma patients, but many patients derive no clinical benefit, and the molecular underpinnings of such resistance remain elusive. Here, we leveraged single-cell RNA-seq (scRNA-seq) from 33 melanoma tumors and computational analyses to interrogate malignant cell states that promote immune evasion. We identified a resistance program expressed by malignant cells that is associated with T-cell exclusion and immune evasion. The program is expressed prior to immunotherapy, characterizes cold niches in situ, and predicts clinical responses to anti-PD-1 therapy in an independent cohort of 112 melanoma patients. CDK4/6-inhibition represses this program in individual malignant cells, induces senescence, and reduces melanoma tumor outgrowth in mouse models in vivo when given in combination with immunotherapy. Our study provides a high-resolution landscape of ICI resistant cell states, identifies clinically predictive signatures, and suggests new therapeutic strategies to overcome immunotherapy resistance. This study will be published on Nov. 1st in Cell (Jerby-Arnon et al., Cell 2018).
This abstract is also being presented as Poster A25.
Citation Format: Parin Shah, Michael Cuoco, Mei-Ju Su, Johannes Melms, Rachel Leeson, Abhay Kanodia, Shaolin Mei, Jia-Ren Lin, Shu Wang, Bokang Rabasha, David Liu, Alex K. Shalek, Itay Tirosh, Peter K. Sorger, Kai Wucherpfennig, Eliezer M. Van Allen, Dirk Schadendorf, Bruce E. Johnson, Asaf Rotem, Orit Rozenblatt-Rosen, Levi A. Garraway, Charles H. Yoon, Benjamin Izar, Aviv Regev, Livnat Jerby-Arnon. A cancer cell program promotes T-cell exclusion and resistance to checkpoint blockade [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr PR01.
Abstract PR12: Regulation of the tumor-suppressive miR-29 family by oncogenic MAPK signaling in melanoma
Authors: Vera Olga , Bok Ilah , Jasani Neel , Balogun Oluwashanu , Nakamura Koji , Karreth Florian 
Published: June 2022

Abstract
MicroRNAs are a group of noncoding RNAs that can regulate gene expression by targeting the mRNA of a gene. Many microRNAs respond to different stimuli such as growth signals or cellular stress. The tumor-suppressive miR-29 family (miR-29a, b and c), for example, is induced during aging and senescence as a p53-dependent response to DNA damage. Given the tumor-suppressive potential of miR-29, we sought to examine if its expression is induced by oncogenic stress in a p53-dependent manner. Ectopic overexpression of oncogenic Braf-V600E and Kras-G12D in mouse embryonic fibroblasts (MEFs) using retroviral transduction resulted in increased expression of pri-miR-29a-b1 and, to a lesser extent, pri-miR-29b2~c. While ectopic Kras-G12D overexpression stimulated p53 activity, Braf-V600E failed to elicit a p53 response, suggesting that this oncogene provokes miR-29 expression in a p53-independent manner. Moreover, expression of Braf-V600E at physiologic levels induced miR-29 in the absence of a p53 response. Accordingly, expression of endogenous Braf-V600E stimulated miR-29 in MEFs even when p53 was silenced by RNAi. When Braf-V600E MEFs were treated with a MEK inhibitor, miR-29 levels decreased in both the presence and absence of p53, suggesting that the MAPK pathway downstream of Braf-V600E directly regulates miR-29 transcription. Importantly, TPA-mediated stimulation of the MAPK pathway increased miR-29 levels in human melanocytes. Similarly, expression of Braf-V600E induced miR-29 in human melanocytes and MEK inhibition rescued this effect. These results strongly support the notion that miR-29 transcription is induced by MAPK signaling and suggest that oncogenic BRAF provokes a tumor-suppressive miR-29 checkpoint that needs to be inactivated for further tumor progression. Indeed, human melanoma cells lines express lower levels of miR-29 compared to human melanocytes, and inactivation of miR-29 by a lentiviral sponge in Braf-V600E mutant melanocytes and melanoma cells promotes cell transformation. We are now utilizing our ESC-GEMM platform to generate Braf-V600E; Pten-deficient mice expressing the miR-29 sponge and will assess if counteracting the induction of miR-29 by Braf-V600E promotes melanoma formation in vivo. Our results suggest a biphasic role of miR-29 during melanomagenesis where Braf-V600E-induced miR-29 upregulation prevents the progression of early lesions until miR-29 is downregulated, likely by inactivation of the ARF-p53 axis.
This abstract is also being presented as Poster B24.
Citation Format: Olga Vera, Ilah Bok, Neel Jasani, Oluwashanu Balogun, Koji Nakamura, Florian Karreth. Regulation of the tumor-suppressive miR-29 family by oncogenic MAPK signaling in melanoma [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr PR12.