Dermatology Commons^™

Xtx101, A Tumor-Activated, Fc-Enhanced Anti-Ctla-4 Monoclonal Antibody, Demonstrates Tumor-Growth Inhibition And Tumor-Selective Pharmacodynamics In Mouse Models Of Cancer, Kurt A. Jenkins, Miso Park, Magali Pederzoli-Ribeil, Ugur Eskiocak, Parker Johnson, Wilson Guzman, Megan Mclaughlin, Deborah Moore-Lai, Caitlin O'Toole, Zhen Liu, Benjamin Nicholson, Veronica Flesch, Huawei Qiu, Tim Clackson, Ronan C. O'Hagan, Ulrich Rodeck, Margaret Karow, Jennifer O'Neil, John C. Williams

Department of Dermatology and Cutaneous Biology Faculty Papers

INTRODUCTION: The clinical benefit of the anti-CTLA-4 monoclonal antibody (mAb) ipilimumab has been well established but limited by immune-related adverse events, especially when ipilimumab is used in combination with anti-PD-(L)1 mAb therapy. To overcome these limitations, we have developed XTX101, a tumor-activated, Fc-enhanced anti-CTLA-4 mAb.

METHODS: XTX101 consists of an anti-human CTLA-4 mAb covalently linked to masking peptides that block the complementarity-determining regions, thereby minimizing the mAb binding to CTLA-4. The masking peptides are designed to be released by proteases that are typically dysregulated within the tumor microenvironment (TME), resulting in activation of XTX101 intratumorally. Mutations within the Fc region …

Advances In Melanoma: Epidemiology, Diagnosis, And Prognosis, Shayan Waseh, Jason B. Lee

Department of Dermatology and Cutaneous Biology Faculty Papers

Unraveling the multidimensional complexities of melanoma has required concerted efforts by dedicated community of researchers and clinicians battling against this deadly form of skin cancer. Remarkable advances have been made in the realm of epidemiology, classification, diagnosis, and therapy of melanoma. The treatment of advanced melanomas has entered the golden era as targeted personalized therapies have emerged that have significantly altered the mortality rate. A paradigm shift in the approach to melanoma classification, diagnosis, prognosis, and staging is underway, fueled by discoveries of genetic alterations in melanocytic neoplasms. A morphologic clinicopathologic classification of melanoma is expected to be replaced by …

High Expression Of Talin-1 Is Associated With Tumor Progression And Recurrence In Melanoma Skin Cancer Patients., Yasaman Rezaie, Fahimeh Fattahi, Baharnaz Mashinchi, Kambiz Kamyab Hesari, Sahar Montazeri, Elham Kalantari, Zahra Madjd, Leili Saeednejad Zanjani

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Talin-1 as a component of multi-protein adhesion complexes plays a role in tumor formation and migration in various malignancies. This study investigated Talin-1 in protein levels as a potential prognosis biomarker in skin tumors.

METHODS: Talin-1 was evaluated in 106 skin cancer (33 melanomas and 73 non-melanomas skin cancer (NMSC)) and 11 normal skin formalin-fixed paraffin-embedded (FFPE) tissue samples using immunohistochemical technique on tissue microarrays (TMAs). The association between the expression of Talin-1 and clinicopathological parameters, as well as survival outcomes, were assessed.

RESULTS: Our findings from data minings through bioinformatics tools indicated dysregulation of Talin-1 in mRNA levels …

In Vivo T Cell Genetic Engineering With Melanoma-Specific Tcr And Car, Toby Mathew, Vitali Alexeev

Phase 1

Introduction: Adoptive cell transfer (ACT) using T cells genetically engineered to express tumor-specific T cell receptors (TCR) and Chimeric Antigen receptors (CAR) have demonstrated high remission rates in patients with advanced cancers. Targeting of metastatic melanoma with TCR-modified recombinant T cells showed clinically significant response in the majority of patients. However, due to certain drawbacks, this powerful strategy is not yet available for broad clinical application. We propose that in vivo genetic engineering approach may allow overcoming several drawbacks associated ACT and could convert it into generic and cost-effective modality to bring recombinant T cell therapies to general patient …

Immune-Mediated Colitis From Dual Checkpoint Inhibitors., Nishanth Thalambedu, Yasir Khan, Qian Zhang, Shristi Khanal, Ammar Ashfaq

Abington Jefferson Health Papers

Melanoma is a deadly disease with immunotherapy treatment options that emerged in the last few years and have changed the disease outcome. However, it is associated with immune-related toxic effects despite improving survival. We present the case of a 53-year-old woman who had two weeks of diarrhea after she was treated with dual immunotherapy agents for her advanced melanoma. The final workup revealed pancolitis, possibly due to immunotherapy adverse effects. Initial conservative treatment, unfortunately, did not lead to a clinical improvement until a steroid was introduced. We are reporting this case to alert our fellow physicians about the immune-mediated toxicities …

Relating The Gut Metagenome And Metatranscriptome To Immunotherapy Responses In Melanoma Patients., Brandilyn A. Peters, Melissa Wilson, Una Moran, Anna Pavlick, Allison Izsak, Todd Wechter, Jeffrey S. Weber, Iman Osman, Jiyoung Ahn

Department of Medical Oncology Faculty Papers

BACKGROUND: Recent evidence suggests that immunotherapy efficacy in melanoma is modulated by gut microbiota. Few studies have examined this phenomenon in humans, and none have incorporated metatranscriptomics, important for determining expression of metagenomic functions in the microbial community.

METHODS: In melanoma patients undergoing immunotherapy, gut microbiome was characterized in pre-treatment stool using 16S rRNA gene and shotgun metagenome sequencing (n = 27). Transcriptional expression of metagenomic pathways was confirmed with metatranscriptome sequencing in a subset of 17. We examined associations of taxa and metagenomic pathways with progression-free survival (PFS) using 500 × 10-fold cross-validated elastic-net penalized Cox regression.

RESULTS: Higher …

Guidance Of Sentinel Lymph Node Biopsy Decisions In Patients With T1-T2 Melanoma Using Gene Expression Profiling., John T. Vetto, Eddy C. Hsueh, Brian R. Gastman, Larry D. Dillon, Federico A. Monzon, Robert W. Cook, Jennifer Keller, Xin Huang, Andrew Fleming, Preston Hewgley, Pedram Gerami, Sancy Leachman, Jeffrey D. Wayne, Adam C. Berger, Martin D. Fleming

Department of Surgery Faculty Papers

AIM: Can gene expression profiling be used to identify patients with T1-T2 melanoma at low risk for sentinel lymph node (SLN) positivity?

PATIENTS & METHODS: Bioinformatics modeling determined a population in which a 31-gene expression profile test predicted <5% SLN positivity. Multicenter, prospectively-tested (n = 1421) and retrospective (n = 690) cohorts were used for validation and outcomes, respectively.

RESULTS: Patients 55-64 years and ≥65 years with a class 1A (low-risk) profile had SLN positivity rates of 4.9% and 1.6%. Class 2B (high-risk) patients had SLN positivity rates of 30.8% and 11.9%. Melanoma-specific survival was 99.3% for patients ≥55 years with class 1A, T1-T2 tumors and 55.0% for class 2B, SLN-positive, T1-T2 tumors.

CONCLUSION: The 31-gene expression profile test identifies patients …

The Role Of Human Papillomaviruses And Polyomaviruses In Braf-Inhibitor Induced Cutaneous Squamous Cell Carcinoma And Benign Squamoproliferative Lesions, Karin J. Purdie, Charlotte M. Proby, Hasan Rizvi, Heather Griffin, John Doorbar, Mary Sommerlad, Mariet C. Feltkamp, Els Van Der Meijden, Gareth J. Inman, Andrew P. South, Irene M. Leigh, Catherine A. Harwood

Department of Dermatology and Cutaneous Biology Faculty Papers

Background: Human papillomavirus (HPV) has long been proposed as a cofactor in the pathogenesis of cutaneous squamous cell carcinoma (cSCC). More recently, the striking clinico-pathological features of cSCCs that complicate treatment of metastatic melanoma with inhibitors targeting BRAF mutations (BRAFi) has prompted speculation concerning a pathogenic role for oncogenic viruses. Here, we investigate HPV and human polyomaviruses (HPyV) and correlate with clinical, histologic, and genetic features in BRAFi-associated cSCC. Materials and Methods: Patients receiving BRAFi treatment were recruited at Barts Health NHS Trust. HPV DNA was detected in microdissected frozen samples using reverse line probe technology and degenerate and nested …

A Preexisting Rare Pik3ca E545k Subpopulation Confers Clinical Resistance To Mek Plus Cdk4/6 Inhibition In Nras Melanoma And Is Dependent On S6k1 Signaling, Gabriele Romano, Pei-Ling Chen, Ping Song, Jennifer L. Mcquade, Roger J. Liang, Mingguang Liu, Whijae Roh, Dzifa Y. Duose, Fernando C.L. Carapeto, Jun Li, Jessica L.F. Teh, Andrew A. Aplin, Merry Chen, Jianhua Zhang, Alexander J. Lazar, Michael A. Davies, P. Andrew Futreal, Rodabe N. Amaria, David Y. Zhang, Jennifer A. Wargo, Lawrence N. Kwong

Department of Cancer Biology Faculty Papers

Combined MEK and CDK4/6 inhibition (MEKi + CDK4i) has shown promising clinical outcomes in patients with NRAS- mutant melanoma. Here, we interrogated longitudinal biopsies from a patient who initially responded to MEKi + CDK4i therapy but subsequently developed resistance. Whole-exome sequencing and functional validation identified an acquired PIK3CA ^E545K mutation as conferring drug resistance. We demonstrate that PIK3CA ^E545K preexisted in a rare subpopulation that was missed by both clinical and research testing, but was revealed upon multiregion sampling due to PIK3CA ^E545K being nonuniformly distributed. This resistant population rapidly expanded after the initiation of MEKi + CDK4i therapy and …

A Comprehensive Patient-Derived Xenograft Collection Representing The Heterogeneity Of Melanoma., Clemens Krepler, Katrin Sproesser, Patricia Brafford, Marilda Beqiri, Bradley Garman, Min Xiao, Batool Shannan, Andrea Watters, Michela Perego, Gao Zhang, Adina Vultur, Xiangfan Yin, Qin Liu, Ioannis N Anastopoulos, Bradley Wubbenhorst, Melissa A. Wilson, Wei Xu, Giorgos Karakousis, Michael Feldman, Xiaowei Xu, Ravi Amaravadi, Tara C. Gangadhar, David E. Elder, Lauren E. Haydu, Jennifer A. Wargo, Michael A. Davies, Yiling Lu, Gordon B. Mills, Dennie T. Frederick, Michal Barzily-Rokni, Keith T. Flaherty, Dave S. Hoon, Michael Guarino, Joseph J. Bennett, Randall W. Ryan, Nicholas J. Petrelli, Carol L. Shields, Mizue Terai, Takami Sato, Andrew E. Aplin, Alexander Roesch, David Darr, Steve Angus, Rakesh Kumar, Ensar Halilovic, Giordano Caponigro, Sebastien Jeay, Jens Wuerthner, Annette Walter, Matthias Ocker, Matthew B. Boxer, Lynn Schuchter, Katherine L Nathanson, Meenhard Herlyn

Kimmel Cancer Center Papers, Presentations, and Grand Rounds

Therapy of advanced melanoma is changing dramatically. Following mutational and biological subclassification of this heterogeneous cancer, several targeted and immune therapies were approved and increased survival significantly. To facilitate further advancements through pre-clinical in vivo modeling, we have established 459 patient-derived xenografts (PDX) and live tissue samples from 384 patients representing the full spectrum of clinical, therapeutic, mutational, and biological heterogeneity of melanoma. PDX have been characterized using targeted sequencing and protein arrays and are clinically annotated. This exhaustive live tissue resource includes PDX from 57 samples resistant to targeted therapy, 61 samples from responders and non-responders to immune checkpoint …

Inhibition Of Age-Related Therapy Resistance In Melanoma By Rosiglitazone-Mediated Induction Of Klotho., Reeti Behera, Amanpreet Kaur, Marie R. Webster, Suyeon Kim, Abibatou Ndoye, Curtis H. Kugel, Gretchen M. Alicea, Joshua Wang, Kanad Ghosh, Phil Cheng, Sofia Lisanti, Katie Marchbank, Vanessa Dang, Mitchell Levesque, Reinhard Dummer, Xiaowei Xu, Meenhard Herlyn, Andrew E. Aplin, Alexander Roesch, Cecilia Caino, Dario C. Altieri, Ashani T. Weeraratna

Department of Cancer Biology Faculty Papers

Purpose: Aging is a poor prognostic factor for melanoma. We have shown that melanoma cells in an aged microenvironment are more resistant to targeted therapy than identical cells in a young microenvironment. This is dependent on age-related secreted factors. Klotho is an age-related protein whose serum levels decrease dramatically by age 40. Most studies on klotho in cancer have focused on the expression of klotho in the tumor cell. We have shown that exogenous klotho inhibits internalization and signaling of Wnt5A, which drives melanoma metastasis and resistance to targeted therapy. We investigate here whether increasing klotho in the aged microenvironment …

Challenges To Smartphone Applications For Melanoma Detection, Jordan V. Wang, Lance W. Chapman, Matthew S. Keller

Department of Dermatology and Cutaneous Biology Faculty Papers

This commentary addresses the emerging market for health-related smartphone applications. Specific to dermatology, there has been a significant increase not only in applications that promote skin cancer awareness and education but also in those meant for detection. With evidence showing that 365 dermatology-related applications were available in 2014--up from 230 in 2012--and that 1 in 5 patients under the age of 50 have used a smartphone to help diagnose a skin problem, there is clearly a large subset of patients participating in this growing trend. Therefore, we are obligated to take a closer look into this phenomenon. Studies have shown …

Rac1 P29s Regulates Pd-L1 Expression In Melanoma., Ha Linh Vu, Sheera Rosenbaum, Timothy J. Purwin, Michael A. Davies, Andrew E. Aplin

Department of Cancer Biology Faculty Papers

Whole exome sequencing of cutaneous melanoma has led to the detection of P29 mutations in RAC1 in 5-9% of samples, but the role of RAC1 P29 mutations in melanoma biology remains unclear. Using reverse phase protein array analysis to examine the changes in protein/phospho-protein expression, we identified cyclin B1, PD-L1, Ets-1, and Syk as being selectively upregulated with RAC1 P29S expression and downregulated with RAC1 P29S depletion. Using the melanoma patient samples in TCGA, we found PD-L1 expression to be significantly increased in RAC1 P29S patients compared to RAC1 WT as well as other RAC1 mutants. The finding that PD-L1 …

Nf-Κb Regulation Of C-Flip Promotes Tnfα-Mediated Raf Inhibitor Resistance In Melanoma., Yongping Shao, Kaitlyn Le, Hanyin Cheng, Andrew E. Aplin

Department of Cancer Biology Faculty Papers

Targeted inhibitors elicit heterogeneous clinical responses in genetically stratified groups of patients. Although most studies focus on tumor intrinsic properties, factors in the tumor microenvironment were recently found to modulate the response to inhibitors. Here, we show that in cutaneous BRAF V600E melanoma, the cytokine tumor necrosis factor-α (TNFα) blocks RAF inhibitor-induced apoptosis via activation of NF-κB. Several NF-κB-dependent factors are upregulated following TNFα and RAF inhibitor treatment. Of these factors, we show that death receptor inhibitor cellular caspase 8 (FLICE)-like inhibitory protein (c-FLIP) is required for TNFα-induced protection against RAF inhibitor. Overexpression of c-FLIP_S or c-FLIP_L isoform decreased RAF …

Altered Drainage Patterns In Patients With Melanoma And Previous Axillary Dissection., Caitlyn M. Johnson, Charles Intenzo, Michael Mastrangelo, Kendra Feeney, Adam C. Berger

Department of Surgery Faculty Papers

The incidence of melanoma is increasing rapidly in the United States. Sentinel lymph node biopsy is an important diagnostic tool in the treatment and staging of melanoma. However, many patients with melanoma will have had lymph node surgery for previous melanoma or breast cancer. We set out to examine alterations in drainage patterns in patients with previous axillary dissection for breast cancer. We reviewed four patients with truncal and/or extremity melanomas and examined their lymphoscintigraphy and drainage patterns. Three patients with truncal melanoma mapped to cervical lymph nodes and a fourth patient with an arm melanoma mapped to her previously …

Mechanisms Of Resistance To Raf Inhibitors In Melanoma., A E Aplin, Fred M Kaplan, Yongping Shao

Department of Cancer Biology Faculty Papers

The recent RAF inhibitor trial with PLX4032/RG7204 in late-stage mutant B-RAF melanoma patients has been lauded as a success story for personalized cancer therapy since short-term clinical responses were observed in the majority of patients. However, initial responses were followed by subsequent tumor re-growth, and a subset of patients showed intrinsic resistance. Bi-directional translational efforts are now essential to determine the mechanisms underlying acquired/secondary and intrinsic resistance to RAF inhibitors.