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Item A Review of Current and Pipeline Drugs for Treatment of Melanoma(MDPI, 2024-02-07) Natarelli, Nicole; Aleman, Sarah J.; Mark, Isabella M.; Tran, Jasmine T.; Kwak, Sean; Botto, Elizabeth; Aflatooni, Shaliz; Diaz, Michael J.; Lipner, Shari R.; Medicine, School of MedicineMalignant melanoma is the most aggressive form of skin cancer. Standard treatment options include surgery, radiation therapy, systemic chemotherapy, targeted therapy, and immunotherapy. Combining these modalities often yields better responses. Surgery is suitable for localized cases, sometimes involving lymph node dissection and biopsy, to assess the spread of the disease. Radiation therapy may be sometimes used as a standalone treatment or following surgical excision. Systemic chemotherapy, while having low response rates, is utilized as part of combination treatments or when other methods fail. The development of resistance to systemic chemotherapies and associated side effects have prompted further research and clinical trials for novel approaches. In the case of advanced-stage melanoma, a comprehensive approach may be necessary, incorporating targeted therapies and immunotherapies that demonstrate significant antitumor activity. Targeted therapies, including inhibitors targeting BRAF, MEK, c-KIT, and NRAS, are designed to block the specific molecules responsible for tumor growth. These therapies show promise, particularly in patients with corresponding mutations. Combination therapy, including BRAF and MEK inhibitors, has been evidenced to improve progression-free survival; however, concerns about resistance and cutaneous toxicities highlight the need for close monitoring. Immunotherapies, leveraging tumor-infiltrating lymphocytes and CAR T cells, enhance immune responses. Lifileucel, an FDA-approved tumor-infiltrating lymphocyte therapy, has demonstrated improved response rates in advanced-stage melanoma. Ongoing trials continue to explore the efficacy of CAR T-cell therapy for advanced melanoma. Checkpoint inhibitors targeting CTLA-4 and PD-1 have enhanced outcomes. Emerging IL-2 therapies boost dendritic cells, enhancing anticancer immunity. Oncolytic virus therapy, approved for advanced melanoma, augments treatment efficacy in combination approaches. While immunotherapy has significantly advanced melanoma treatment, its success varies, prompting research into new drugs and factors influencing outcomes. This review provides insights into current melanoma treatments and recent therapeutic advances.Item ALDH1 Bio-activates Nifuroxazide to Eradicate ALDHHigh Melanoma-Initiating Cells(Elsevier, 2018-12-20) Sarvi, Sana; Crispin, Richard; Lu, Yuting; Zeng, Lifan; Hurley, Thomas D.; Houston, Douglas R.; von Kriegsheim, Alex; Chen, Che-Hong; Mochly-Rosen, Daria; Ranzani, Marco; Mathers, Marie E.; Xu, Xiaowei; Xu, Wei; Adams, David J.; Carragher, Neil O.; Fujita, Mayumi; Schuchter, Lynn; Unciti-Broceta, Asier; Brunton, Valerie G.; Patton, E. Elizabeth; Biochemistry and Molecular Biology, School of Medicine5-Nitrofurans are antibiotic pro-drugs that have potential as cancer therapeutics. Here, we show that 5-nitrofurans can be bio-activated by aldehyde dehydrogenase (ALDH) 1A1/1A3 enzymes that are highly expressed in a subpopulation of cancer-initiating (stem) cells. We discover that the 5-nitrofuran, nifuroxazide, is selective for bio-activation by ALDH1 isoforms over ALDH2, whereby it both oxidizes ALDH1 and is converted to cytotoxic metabolites in a two-hit pro-drug mechanism. We show that ALDH1High melanoma cells are sensitive to nifuroxazide, while ALDH1A3 loss-of-function mutations confer drug resistance. In tumors, nifuroxazide targets ALDH1High melanoma subpopulations with the subsequent loss of melanoma-initiating cell potential. BRAF and MEK inhibitor therapy increases ALDH1 expression in patient melanomas, and effectively combines with nifuroxazide in melanoma cell models. The selective eradication of ALDH1High cells by nifuroxazide-ALDH1 activation goes beyond current strategies based on inhibiting ALDH1 and provides a rational basis for the nifuroxazide mechanism of action in cancer.Item The Association Between Citrus Consumption and Skin Cancer: An Analysis of Risk and Nutrient-Gene Interaction(2020-12) Marley, Andrew Raymond; Han, Jiali; Sibg, Yiqing; Li, Xin; Li, Ming; Champion, Victoria L.Purpose. In the US, melanoma and non-melanoma skin cancer (NMSC) rates have increased substantially in recent decades. While many skin cancer risk factors have been established, the impact of dietary citrus, which is naturally abundant in photocarcinogenic psoralens, remains enigmatic. The purpose of this research was to investigate associations between citrus consumption and risks of melanoma and NMSC, and to conduct a genome-wide study to identify genetic variants that may modify this association. Methods. Participants from the UK Biobank were leveraged for these analyses. Citrus consumption was collected via five rounds of 24-hour recall questionnaires, with complete citrus data available for n=210,126 participants. Ascertainment of melanoma and NMSC cases were identified by international classification of disease codes via linkage with national registries. Logistic regression was used to estimate odds ratios and 95% confidence intervals for the associations between citrus consumption and skin cancer outcomes. Individual citrus products were assessed for independent associations with skin cancer risk, and established skin cancer risk factors were tested for interaction. Joint 2-degree-of-freedom (df) and 1-df tests were used to assess interaction between total citrus consumption and genetic variants. Results. After controlling for covariates, high total citrus consumption was significantly associated with increased melanoma risk, an association primarily driven by orange and orange juice consumption. Skin color was found to be a significant effect modifier for the association between total citrus consumption and melanoma risk, but only before adjusting for multiple comparisons. No significant associations were observed for high total citrus consumption or consumption of any individual citrus products and NMSC risk. Significant associations for half a serving of citrus consumption and NMSC risk were likely due to chance or confounding. Index SNPs on chromosomes 3, 9, and 16 were significant according to the joint 2-df test, and 7 SNPs on chromosome 16 displayed evidence of a citrus-gene interaction. Conclusion. My analyses provide evidence in support of high citrus consumption significantly increasing risk of melanoma, but not NMSC. I also identified SNPs on AFG3L1P that may modify this association. Future research should further explore these associations, particularly for NMSC and to confirm my genetic findings.Item Burden and Risk Factors of Brain Metastases in Melanoma: A Systematic Literature Review(MDPI, 2022-12-12) Tan, Xiang-Lin; Le, Amy; Tang, Huilin; Brown, Madeline; Scherrer, Emilie; Han, Jiali; Jiang, Ruixuan; Diede, Scott J.; Shui, Irene M.; Epidemiology, School of Public HealthMelanoma can frequently metastasize to the brain with severe consequences. However, variation of melanoma brain metastases (MBM) development among populations is not well studied, and underlying mechanisms and risk factors for MBM development are not consistently documented. We conducted a systematic literature review (SLR) including a total of 39 articles to evaluate the proportion of melanoma patients who are diagnosed with, or develop, brain metastases, and summarize the risk factors of MBM. The average proportion of MBM was calculated and weighted by the sample size of each study. Meta-analyses were conducted for the selected risk factors using a random-effects model. The proportion of MBM at diagnosis was 33% (975 with MBM out of 2948 patients) among patients with cutaneous melanoma (excluding acral) and 23% (651/2875) among patients with cutaneous mixed with other types of melanoma. The proportion at diagnosis was lower among populations with mucosal (9/96, 9%) or uveal (4/184, 2%) melanoma and among populations outside the United States and Europe. Meta-analysis demonstrated that male vs. female gender and left-sided tumors vs. right-sided were significantly associated with increased risk of melanoma brain metastases. These data may help clinicians to assess an individual patient's risk of developing melanoma brain metastases.Item Caffeine Intake, Coffee Consumption, and Risk of Cutaneous Malignant Melanoma(Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins, 2015-11) Wu, Shaowei; Han, Jiali; Song, Fengju; Cho, Eunyoung; Gao, Xiang; Hunter, David J.; Qureshi, Abrar A.; Department of Epidemiology, Richard M. Fairbanks School of Public HealthBACKGROUND: Caffeine has been shown to prevent ultraviolet radiation-induced carcinogenesis and to inhibit growth of melanoma cells in experimental studies. We evaluated the association among caffeine intake, coffee consumption, and melanoma risk among three large cohort studies. METHODS: The analysis used data from 89,220 women in the Nurses' Health Study II (1991-2009), 74,666 women in the Nurses' Health Study (1980-2008), and 39,424 men in the Health Professionals Follow-up Study (1986-2008). We used Cox proportional hazards models to estimate the hazard ratios (HR) with 95% confidence intervals (CIs) of melanoma associated with dietary intakes. RESULTS: We documented 2,254 melanoma cases over 4 million person-years of follow-up. After adjustment for other risk factors, higher total caffeine intake was associated with a lower risk of melanoma (≥393 mg/day vs. <60 mg/day: HR = 0.78, 95% CI = 0.64, 0.96; Ptrend = 0.048). The association was more apparent in women (≥393 mg/day vs. <60 mg/day: HR = 0.70, 95% CI = 0.58, 0.85; Ptrend = 0.001) than in men (HR = 0.94, 95% CI = 0.75, 1.2; Ptrend = 0.81), and more apparent for melanomas occurring on body sites with higher continuous sun exposure (head, neck, and extremities; ≥393 mg/day vs. <60 mg/day: HR = 0.71, 95% CI = 0.59, 0.86; Ptrend = 0.001) than for melanomas occurring on body sites with lower continuous sun exposure (trunk including shoulder, back, hip, abdomen, and chest; HR = 0.90, 95% CI = 0.70, 1.2; Ptrend = 0.60). This pattern of association was similar to that for caffeinated coffee consumption, whereas no association was found for decaffeinated coffee consumption and melanoma risk. CONCLUSIONS: Increasing caffeine intake and caffeinated coffee consumption is associated with decreased risk of cutaneous malignant melanomas.Item CD4+ T cell mediated tumor immunity following transplantation of TRP-1 TCR gene modified hematopoietic stem cells(2013-12-10) Ha, Sung Pil; Touloukian, Christopher E.; Broxmeyer, Hal E.; Gardner, Thomas A.; Harrington, Maureen A.; He, Johnny J.Immunotherapy for cancer has held much promise as a potent modality of cancer treatment. The ability to selectively destroy diseased cells and leave healthy cells unharmed has been the goal of cancer immunotherapy for the past thirty years. However, the full capabilities of cancer immunotherapies have been elusive. Cancer immunotherapies have been consistently hampered by limited immune reactivity, a diminishing immune response over time, and a failure to overcome self-tolerance. Many of these deficiencies have been borne-out by immunotherapies that have focused on the adoptive transfer of activated or genetically modified mature CD8+ T cells. The limitations inherent in therapies involving terminally differentiated mature lymphocytes include limited duration, lack of involvement of other components of the immune system, and limited clinical efficacy. We sought to overcome these limitations by altering and enhancing long-term host immunity by genetically modifying then transplanting HSCs. To study these questions and test the efficiency of gene transfer, we cloned a tumor reactive HLA-DR4-restricted CD4+ TCR specific for the melanocyte differentiation antigen TRP-1, then constructed both a high expression lentiviral delivery system and a TCR Tg expressing the same TCR genes. We demonstrate with both mouse and human HSCs durable, high-efficiency TCR gene transfer, following long-term transplantation. We demonstrate the induction of spontaneous autoimmune vitiligo and a TCR-specific TH1 polarized memory effector CD4+ T cell population. Most importantly, we demonstrate the destruction of subcutaneous melanoma without the aid of vaccination, immune modulation, or cytokine administration. Overall, these results demonstrate the creation of a novel translational model of durable lentiviral gene transfer, the induction of spontaneous CD4+ T cell immunity, the breaking of self-tolerance, and the induction of anti-tumor immunity.Item Characterization and initial demonstration of in vivo efficacy of a novel heat-activated metalloenediyne anti-cancer agent(Taylor & Francis, 2022) Garrett, Joy; Metzger, Erin; Dewhirst, Mark W.; Pollok, Karen E.; Turchi, John J.; Le Poole, Isabelle C.; Couch, Kira; Lew, Logan; Sinn, Anthony; Zaleski, Jeffrey M.; Dynlacht, Joseph R.; Radiation Oncology, School of MedicineBackground: Enediynes are anti-cancer agents that are highly cytotoxic due to their propensity for low thermal activation of radical generation. The diradical intermediate produced from Bergman cyclization of the enediyne moiety may induce DNA damage and cell lethality. The cytotoxicity of enediynes and difficulties in controlling their thermal cyclization has limited their clinical use. We recently showed that enediyne toxicity at 37 °C can be mitigated by metallation, but cytotoxic effects of 'metalloenediynes' on cultured tumor cells are potentiated by hyperthermia. Reduction of cytotoxicity at normothermia suggests metalloenediynes will have a large therapeutic margin, with cell death occurring primarily in the heated tumor. Based on our previous in vitro findings, FeSO4-PyED, an Fe co-factor complex of (Z)-N,N'-bis[1-pyridin-2-yl-meth-(E)-ylidene]oct-4-ene-2,6-diyne-1,8-diamine, was prioritized for further in vitro and in vivo testing in normal human melanocytes and melanoma cells. Methods: Clonogenic survival, apopotosis and DNA binding assays were used to determine mechanisms of enhancement of FeSO4-PyED cytotoxicity by hyperthermia. A murine human melanoma xenograft model was used to assess in vivo efficacy of FeSO4-PyED at 37 or 42.5 °C. Results: FeSO4-PyED is a DNA-binding compound. Enhancement of FeSO4-PyED cytotoxicity by hyperthermia in melanoma cells was due to Bergman cyclization, diradical formation, and increased apoptosis. Thermal enhancement, however, was not observed in melanocytes. FeSO4-PyED inhibited tumor growth when melanomas were heated during drug treatment, without inducing normal tissue damage. Conclusion: By leveraging the unique thermal activation properties of metalloenediynes, we propose that localized moderate hyperthermia can be used to confine the cytotoxicity of these compounds to tumors, while sparing normal tissue.Item Characterization of Thermally Activated Metalloenediyne Cytotoxicity in Human Melanoma Cells(BioOne, 2018-08) Keller, Eric J.; Porter, Meghan; Garrett, Joy E.; Varie, Meredith; Wang, Haiyan; Pollok, Karen E.; Turchi, John J.; Zaleski, Jeffrey M.; Dynlacht, Joseph R.; Radiation Oncology, School of MedicineEnediynes are a highly cytotoxic class of compounds. However, metallation of these compounds may modulate their activation, and thus their cytotoxicity. We previously demonstrated that cytotoxicity of two different metalloenediynes, including (Z)-N,N'-bis[1-pyridyl-2-yl-meth-(E)-ylidene]octa-4-ene-2,6-diyne-1,8-diamine] (PyED), is potentiated when the compounds are administered to HeLa cells during hyperthermia treatment at concentrations that are minimally or not cytotoxic at 37°C. In this study, we further characterized the concentration, time and temperature dependence of cytotoxicity of PyED on human U-1 melanoma cells. We also investigated the potential mechanisms by which PyED cytotoxicity is enhanced during hyperthermia treatment. Cell killing with PyED was dependent on concentration, temperature during treatment and time of exposure. Potentiation of cytotoxicity was observed when cells were treated with PyED at temperatures ≥39.5°C, and enhancement of cell killing increased with temperature and with increasing time at a given temperature. All cells treated with PyED were shown to have DNA damage, but substantially more damage was observed in cells treated with PyED during heating. DNA repair was also inhibited in cells treated with the drug during hyperthermia. Thus, potentiation of PyED cytotoxicity by hyperthermia may be due to enhancement of drug-induced DNA lesions, and/or the inhibition of repair of sublethal DNA damage. While the selective thermal activation of PyED supports the potential clinical utility of metalloenediynes as cancer thermochemotherapeutic agents, therapeutic gain could be optimized by identifying compounds that produce minimal toxicity at 37°C but which become activated and show enhancement of cytotoxicity within a tumor subjected to localized hyperthermic or thermal ablative treatment, or which might act as bifunctional agents. We thus also describe the development and initial characterization of a novel cofactor complex of PyED, platinated PyED (Pt-PyED). Pt-PyED binds to DNA-like cisplatin, and much like PyED, cytotoxicity is greatly enhanced after treatment with the drug at elevated temperatures. However, in contrast to PyED, Pt-PyED is only minimally cytotoxic at 37°C, at concentrations at which cytotoxicity is enhanced by hyperthermia. Further development of cisplatin-based enediynes may result in compounds which, when activated, will possess multiple DNA binding modalities similar to cisplatin, but produce less side effects in tissues at normothermic temperatures.Item Citrus Consumption and Risk of Non-Melanoma Skin Cancer in the UK Biobank(Taylor & Francis, 2022) Marley, Andrew R.; Li, Ming; Champion, Victoria L.; Song, Yiqing; Han, Jiali; Li, Xin; Epidemiology, School of Public HealthBackground: Non-melanoma skin cancer (NMSC) incidence has been dramatically increasing worldwide. Psoralen, a known photocarcinogen, is naturally abundant in citrus products, leading to the hypothesis that high citrus consumption may increase NMSC risk. Methods: We fitted age- and multivariable-adjusted logistic regression models to evaluate the association between citrus consumption and NMSC risk among 197,372 UKBB participants. A total of 9,613 NMSC cases were identified using International Classification of Disease 10 codes. Citrus consumption data were collected via five rounds of 24-hour recall questionnaires. Results: We found no association between high total citrus consumption and NMSC risk, although a slightly elevated NMSC risk was observed among participants who consumed >0 to half a serving of total citrus per day (OR [95% CI] = 1.08 [1.01-1.16]). There was no association between individual citrus products and NMSC risk. Conclusion: High citrus consumption was not associated with an increased risk of NMSC in our UKBB sample. Further studies are needed to clarify these associations. Supplemental data for this article is available online at https://doi.org/10.1080/01635581.2021.1952439 .Item Citrus-Gene Interaction and Melanoma Risk in the UK Biobank(Wiley, 2022) Marley, Andrew R.; Li, Ming; Champion, Victoria L.; Song, Yiqing; Han, Jiali; Li, Xin; Epidemiology, School of Public HealthHigh citrus consumption may increase melanoma risk; however, little is known about the biological mechanisms of this association, or whether it is modified by genetic variants. We conducted a genome-wide analysis of gene-citrus consumption interactions on melanoma risk among 1563 melanoma cases and 193 296 controls from the UK Biobank. Both the 2-degrees-of-freedom (df) joint test of genetic main effect and gene-environment (G-E) interaction and the standard 1-df G-E interaction test were performed. Three index SNPs (lowest P-value SNP among highly correlated variants [r2 > .6]) were identified from among the 365 genome-wide significant 2-df test results (rs183783391 on chromosome 3 [MITF], rs869329 on chromosome 9 [MTAP] and rs11446223 on chromosome 16 [DEF8]). Although all three were statistically significant for the 2-df test (4.25e-08, 1.98e-10 and 4.93e-13, respectively), none showed evidence of interaction according to the 1-df test (P = .73, .24 and .12, respectively). Eight nonindex, 2-df test significant SNPs on chromosome 16 were significant (P < .05) according to the 1-df test, providing evidence of citrus-gene interaction. Seven of these SNPs were mapped to AFG3L1P (rs199600347, rs111822773, rs113178244, rs3803683, rs73283867, rs78800020, rs73283871), and one SNP was mapped to GAS8 (rs74583214). We identified several genetic loci that may elucidate the association between citrus consumption and melanoma risk. Further studies are needed to confirm these findings.