Medicine and Health Sciences Commons^™

Mutational Patterns In Chemotherapy Resistant Muscle-Invasive Bladder Cancer., David Liu, Philip Abbosh, Daniel Keliher, Brendan Reardon, Diana Miao, Kent Mouw, Amaro Weiner-Taylor, Stephanie Wankowicz, Garam Han, Min Yuen Teo, Catharine Cipolla, Jaegil Kim, Gopa Iyer, Hikmat Al-Ahmadie, Essel Dulaimi, David Y.T. Chen, R. Katherine Alpaugh, Jean Hoffman-Censits, Levi A. Garraway, Gad Getz, Scott L. Carter, Joaquim Bellmunt, Elizabeth R. Plimack, Jonathan E. Rosenberg, Eliezer M. Van Allen

Department of Medical Oncology Faculty Papers

Despite continued widespread use, the genomic effects of cisplatin-based chemotherapy and implications for subsequent treatment are incompletely characterized. Here, we analyze whole exome sequencing of matched pre- and post-neoadjuvant cisplatin-based chemotherapy primary bladder tumor samples from 30 muscle-invasive bladder cancer patients. We observe no overall increase in tumor mutational burden post-chemotherapy, though a significant proportion of subclonal mutations are unique to the matched pre- or post-treatment tumor, suggesting chemotherapy-induced and/or spatial heterogeneity. We subsequently identify and validate a novel mutational signature in post-treatment tumors consistent with known characteristics of cisplatin damage and repair. We find that post-treatment tumor heterogeneity predicts …

Site-Specific Selection Reveals Selective Constraints And Functionality Of Tumor Somatic Mtdna Mutations., Deyang Li, Xiaohong Du, Xu Guo, Lei Zhan, Xin Li, Chun Yin, Cheng Chen, Mingkun Li, Bingshan Li, Hushan Yang, Jinliang Xing

Department of Medical Oncology Faculty Papers

BACKGROUND: Previous studies have indicated that tumor mitochondrial DNA (mtDNA) mutations are primarily shaped by relaxed negative selection, which is contradictory to the critical roles of mtDNA mutations in tumorigenesis. Therefore, we hypothesized that site-specific selection may influence tumor mtDNA mutations.

METHODS: To test our hypothesis, we developed the largest collection of tumor mtDNA mutations to date and evaluated how natural selection shaped mtDNA mutation patterns.

RESULTS: Our data demonstrated that both positive and negative selections acted on specific positions or functional units of tumor mtDNAs, although the landscape of these mutations was consistent with the relaxation of negative selection. …

The Role Of B Cell Targeting In Chronic Graft-Versus-Host Disease., Ruben Rhoades, Md, Sameh Gaballa, Md

Department of Medical Oncology Faculty Papers

Chronic graft-versus-host disease (cGVHD) is a leading cause of late morbidity and mortality following allogeneic stem cell transplantation. Current therapies, including corticosteroids and calcineurin inhibitors, are only effective in roughly 50% of cases; therefore, new treatment strategies are under investigation. What was previously felt to be a T cell disease has more recently been shown to involve activation of both T and B cells, as well as a number of cytokines. With a better understanding of its pathophysiology have come more expansive preclinical and clinical trials, many focused on B cell signaling. This report briefly reviews our current understanding of …

Cabazitaxel In The Treatment Of Metastatic Castration-Resistant Prostate Cancer: Patient Selection And Special Considerations., Sheel Patel, Jean Hoffman-Censits

Department of Medical Oncology Faculty Papers

Cabazitaxel is an effective chemotherapeutic agent used in the treatment of metastatic castration-resistant prostate cancer (mCRPC) refractory to docetaxel. With the advent of new antiandrogen therapies, immune-based treatments, and radioactive-targeted therapy, there are now multiple effective and approved agents for this disease state. The optimal sequencing of these agents is unclear as there are no large-scale head-to-head comparisons. Clinicians must familiarize themselves with the most recent studies as well as drug toxicities to determine the best treatment option for their patients. In this review, we focus on the development of cabazitaxel for mCRPC, evaluate its efficacy, and highlight key strategies …

Prognostic Value Of Routine Laboratory Variables In Prediction Of Breast Cancer Recurrence., Zhu Zhu, Ling Li, Zhong Ye, Tong Fu, Ye Du, Aiping Shi, Di Wu, Ke Li, Yifan Zhu, Chun Wang, Zhimin Fan

Department of Medical Oncology Faculty Papers

The prognostic value of routine laboratory variables in breast cancer has been largely overlooked. Based on laboratory tests commonly performed in clinical practice, we aimed to develop a new model to predict disease free survival (DFS) after surgical removal of primary breast cancer. In a cohort of 1,596 breast cancer patients, we analyzed the associations of 33 laboratory variables with patient DFS. Based on 3 significant laboratory variables (hemoglobin, alkaline phosphatase, and international normalized ratio), together with important demographic and clinical variables, we developed a prognostic model, achieving the area under the curve of 0.79. We categorized patients into 3 …

Differential And Joint Effects Of Metformin And Statins On Overall Survival Of Elderly Patients With Pancreatic Adenocarcinoma: A Large Population-Based Study., Jian-Yu E, Shou-En Lu, Yong Lin, Judith M. Graber, David Rotter, Lanjing Zhang, Gloria M. Petersen, Kitaw Demissie, Grace Lu-Yao, Xiang-Lin Tan

Department of Medical Oncology Faculty Papers

Background: Published evidence indicates that individual use of metformin and statin is associated with reduced cancer mortality. However, their differential and joint effects on pancreatic cancer survival are inconclusive.Methods: We identified a large population-based cohort of 12,572 patients ages 65 years or older with primary pancreatic ductal adenocarcinoma (PDAC) diagnosed between 2008 and 2011 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database. Exposure to metformin and statins was ascertained from Medicare Prescription Drug Event files. Cox proportional hazards models with time-varying covariates adjusted for propensity scores were used to assess the association while controlling for potential confounders.Results: Of 12,572 …

Phase Ib/Ii Study Of The Safety And Efficacy Of Combination Therapy With Multikinase Vegf Inhibitor Pazopanib And Mek Inhibitor Trametinib In Advanced Soft Tissue Sarcoma., Vivek Subbiah, Christian Meyer, Ralph G. Zinner, Funda Meric-Bernstam, Marianna L. Zahurak, Ashley O'Connor, Jason Roszik, Kenna Shaw, Joseph A. Ludwig, Razelle Kurzrock, Nilofe A. Azad

Department of Medical Oncology Faculty Papers

Purpose: Pazopanib, a multireceptor tyrosine kinase inhibitor targeting primarily VEGFRs1–3, is approved for advanced soft tissue sarcoma (STS) and renal cell cancer. Downstream of VEGFR, trametinib is an FDA-approved MEK inhibitor used for melanoma. We hypothesized that vertical pathway inhibition using trametinib would synergize with pazopanib in advanced STS. Experimental Design: In an open-label, multicenter, investigator-initiated National Comprehensive Cancer Network (NCCN)-sponsored trial, patients with metastatic or advanced STS received pazopanib 800 mg and 2 mg of trametinib continuously for 28-day cycles. The primary endpoint was 4-month progression-free survival (PFS). Secondary endpoints were overall survival, response rate, and disease control rate. …

New Interleukin-15 Superagonist (Il-15sa) Significantly Enhances Graft-Versus-Tumor Activity., Cavan P Bailey, Tulin Budak-Alpdogan, Christopher T Sauter, Michelle M Panis, Cihangir Buyukgoz, Emily K Jeng, Hing C Wong, Neal Flomenberg, Md, Onder Alpdogan

Department of Medical Oncology Faculty Papers

Interleukin-15 (IL-15) is a potent cytokine that increases CD8+ T and NK cell numbers and function in experimental models. However, obstacles remain in using IL-15 therapeutically, specifically its low potency and short in vivo half-life. To help overcome this, a new IL-15 superagonist complex comprised of an IL-15N72D mutation and IL-15RαSu/Fc fusion (IL-15SA, also known as ALT-803) was developed. IL-15SA exhibits a significantly longer serum half-life and increased in vivo activity against various tumors. Herein, we evaluated the effects of IL-15SA in recipients of allogeneic hematopoietic stem cell transplantation. Weekly administration of IL-15SA to transplant recipients significantly increased the number …

Establishment Of An Orthotopic Patient-Derived Xenograft Mouse Model Using Uveal Melanoma Hepatic Metastasis., Ken Kageyama, Masahiro Ohara, Kengo Saito, Shinji Ozaki, Mizue Terai, Michael J. Mastrangelo, Paolo Fortina, Andrew E. Aplin, Takami Sato

Department of Medical Oncology Faculty Papers

BACKGROUND: Metastatic uveal melanoma is a highly fatal disease; most patients die from their hepatic metastasis within 1 year. A major drawback in the development of new treatments for metastatic uveal melanoma is the difficulty in obtaining appropriate cell lines and the lack of appropriate animal models. Patient-derived xenograft (PDX) tumor models, bearing ectopically implanted tumors at a subcutaneous site, have been developed. However, these ectopically implanted PDX models have obstacles to translational research, including a low engraftment rate, slow tumor growth, and biological changes after multiple passages due to the different microenvironment. To overcome these limitations, we developed a …

Blimp-1 Impairs T Cell Function Via Upregulation Of Tigit And Pd-1 In Patients With Acute Myeloid Leukemia., Liuluan Zhu, Yaxian Kong, Jianhong Zhang, David F. Claxton, W. Christopher Ehmann, Witold B. Rybka, Neil D. Palmisiano, Ming Wang, Bei Jia, Michael Bayerl, Todd D. Schell, Raymond J. Hohl, Hui Zeng, Hong Zheng

Department of Medical Oncology Faculty Papers

BACKGROUND: T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) and programmed cell death protein 1 (PD-1) are important inhibitory receptors that associate with T cell exhaustion in acute myeloid leukemia (AML). In this study, we aimed to determine the underlying transcriptional mechanisms regulating these inhibitory pathways. Specifically, we investigated the role of transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1) in T cell response and transcriptional regulation of TIGIT and PD-1 in AML.

METHODS: Peripheral blood samples collected from patients with AML were used in this study. Blimp-1 expression was examined by flow cytometry. The correlation of …

Evidence-Based Treatment Options In Recurrent And/Or Metastatic Squamous Cell Carcinoma Of The Head And Neck., Athanassios Argiris, Kevin J. Harrington, Makoto Tahara, Jeltje Schulten, Pauline Chomette, Ana Ferreira Castro, Lisa Licitra

Department of Medical Oncology Faculty Papers

The major development of the past decade in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) was the introduction of cetuximab in combination with platinum plus 5-fluorouracil chemotherapy (CT), followed by maintenance cetuximab (the "EXTREME" regimen). This regimen is supported by a phase 3 randomized trial and subsequent observational studies, and it confers well-documented survival benefits, with median survival ranging between approximately 10 and 14 months, overall response rates between 36 and 44%, and disease control rates of over 80%. Furthermore, as indicated by patient-reported outcome measures, the addition of cetuximab …

Improved Survival After Acute Graft-Versus-Host Disease Diagnosis In The Modern Era., Hanna J. Khoury, Tao Wang, Michael T. Hemmer, Daniel Couriel, Amin Alousi, Corey Cutler, Mahmoud Aljurf, Joseph H Antin, Mouhab Ayas, Minoo Battiwalla, Jean-Yves Cahn, Mitchell Cairo, Yi-Bin Chen, Robert Peter Gale, Shahrukh Hashmi, Robert J. Hayashi, Madan Jagasia, Mark Juckett, Rammurti T. Kamble, Mohamed Kharfan-Dabaja, Mark Litzow, Navneet Majhail, Alan Miller, Taiga Nishihori, Muna Qayed, Helene Schoemans, Harry C. Schouten, Gerard Socie, Jan Storek, Leo Verdonck, Ravi Vij, William A. Wood, Lolie Yu, Rodrigo Martino, Matthew Carabasi, Christopher Dandoy, Usama Gergis, Peiman Hematti, Melham Solh, Kareem Jamani, Leslie Lehmann, Bipin Savani, Kirk R. Schultz, Baldeep M. Wirk, Stephen Spellman, Mukta Arora, Joseph Pidala

Department of Medical Oncology Faculty Papers

A cute graft-versus-host disease remains a major threat to a successful outcome after allogeneic hematopoietic cell transplantation. While improvements in treatment and supportive care have occurred, it is unknown whether these advances have resulted in improved outcome specifically among those diagnosed with acute graft-versus-host disease. We examined outcome following diagnosis of grade II-IV acute graft-versus-host disease according to time period, and explored effects according to original graft-versus-host disease prophylaxis regimen and maximum overall grade of acute graft-versus-host disease. Between 1999 and 2012, 2,905 patients with acute myeloid leukemia (56%), acute lymphoblastic leukemia (30%) or myelodysplastic syndromes (14%) received a sibling …

Mct1 In Invasive Ductal Carcinoma: Monocarboxylate Metabolism And Aggressive Breast Cancer., Jennifer M. Johnson, Paolo Cotzia, Roberto Fratamico, Lekha Mikkilineni, Jason Chen, Daniele Colombo, Mehri Mollaee, Diana Whitaker-Menezes, Marina Domingo-Vidal, Zhao Lin, Tingting Zhan, Madalina Tuluc, Juan P. Palazzo, Ruth C. Birbe, Ubaldo E. Martinez-Outshoorn

Department of Medical Oncology Faculty Papers

Introduction: Monocarboxylate transporter 1 (MCT1) is an importer of monocarboxylates such as lactate and pyruvate and a marker of mitochondrial metabolism. MCT1 is highly expressed in a subgroup of cancer cells to allow for catabolite uptake from the tumor microenvironment to support mitochondrial metabolism. We studied the protein expression of MCT1 in a broad group of breast invasive ductal carcinoma specimens to determine its association with breast cancer subtypes and outcomes. Methods: MCT1 expression was evaluated by immunohistochemistry on tissue micro-arrays (TMA) obtained through our tumor bank. Two hundred and fifty-seven cases were analyzed: 180 cases were estrogen receptor and/or …

Characterizing And Prognosticating Chronic Lymphocytic Leukemia In The Elderly: Prospective Evaluation On 455 Patients Treated In The United States., Chadi Nabhan, Anthony Mato, Christopher R. Flowers, David L. Grinblatt, Nicole Lamanna, Mark A. Weiss, Matthew S. Davids, Arlene S. Swern, Shriya Bhushan, Kristen Sullivan, E. Dawn Flick, Pavel Kiselev, Jeff P. Sharman

Department of Medical Oncology Faculty Papers

BACKGROUND: Median age at diagnosis of patients with chronic lymphocytic leukemia (CLL) is > 70 years. However, the majority of clinical trials do not reflect the demographics of CLL patients treated in the community. We examined treatment patterns, outcomes, and disease-related mortality in patients ≥ 75 years with CLL (E-CLL) in a real-world setting.

METHODS: The Connect® CLL registry is a multicenter, prospective observational cohort study, which enrolled 1494 adult patients between 2010-2014, at 199 US sites. Patients with CLL were enrolled within 2 months of initiating first line of therapy (LOT1) or a subsequent LOT (LOT ≥ 2). Kaplan-Meier methods …

Zoledronic Acid Alters Hematopoiesis And Generates Breast Tumor-Suppressive Bone Marrow Cells., Jessalyn M. Ubellacker, Marie-Therese Haider, Molly J. Decristo, Gloria Allocca, Nicola J. Brown, Daniel P. Silver, Ingunn Holen, Sandra S. Mcallister

Department of Medical Oncology Faculty Papers

BACKGROUND: The bone-targeting agent zoledronic acid (ZOL) increases breast cancer survival in subsets of patients, but the underlying reasons for this protective effect are unknown. ZOL modulates the activity of osteoclasts and osteoblasts, which form hematopoietic stem cell niches, and therefore may affect hematopoietic cells that play a role in breast cancer progression.

METHOD: Immunocompetent and immunocompromised strains of mice commonly used for breast cancer research were injected with a single, clinically relevant dose of ZOL (100 μg/kg) or vehicle control. The effects of ZOL on the bone marrow microenvironment (bone volume, bone cell number/activity, extracellular matrix composition) were established …

Targeting Cancer Stem Cell Propagation With Palbociclib, A Cdk4/6 Inhibitor: Telomerase Drives Tumor Cell Heterogeneity., Gloria Bonuccelli, Maria Peiris-Pages, Bela Ozsvari, Ubaldo E. Martinez-Outshoorn, Federica Sotgia, Michael P Lisanti

Department of Medical Oncology Faculty Papers

In this report, we systematically examined the role of telomerase activity in lung and ovarian cancer stem cell (CSC) propagation. For this purpose, we indirectly gauged telomerase activity, by linking the hTERT-promoter to eGFP. Using lung (A549) and ovarian (SKOV3) cancer cells, transduced with the hTERT-GFP reporter, we then employed GFP-expression levels to fractionate these cell lines into GFP-high and GFP-low populations. We functionally compared the phenotype of these GFP-high and GFP-low populations. More specifically, we now show that the cancer cells with higher telomerase activity (GFP-high) are more energetically activated, with increased mitochondrial mass and function, as well as …