Genetic Phenomena Commons^™

Lfa-1 Activation Enriches Tumor-Specific T Cells In A Cold Tumor Model And Synergizes With Ctla-4 Blockade, Amber Hickman, Joost Koetsier, Trevin Kurtanich, Michael C Nielsen, Glenn Winn, Yunfei Wang, Salah-Eddine Bentebibel, Leilei Shi, Simone Punt, Leila Williams, Cara Haymaker, Charles B Chesson, Faisal Fa'ak, Ana L Dominguez, Richard Jones, Isere Kuiatse, Amy R Caivano, Sayadeth Khounlo, Navin D Warier, Upendra Marathi, Robert V Market, Ronald J Biediger, John W Craft, Patrick Hwu, Michael A Davies, Darren G Woodside, Peter Vanderslice, Adi Diab, Willem W Overwijk, Yared Hailemichael

Faculty, Staff and Student Publications

The inability of CD8+ effector T cells (Teffs) to reach tumor cells is an important aspect of tumor resistance to cancer immunotherapy. The recruitment of these cells to the tumor microenvironment (TME) is regulated by integrins, a family of adhesion molecules that are expressed on T cells. Here, we show that 7HP349, a small-molecule activator of lymphocyte function-associated antigen-1 (LFA-1) and very late activation antigen-4 (VLA-4) integrin cell-adhesion receptors, facilitated the preferential localization of tumor-specific T cells to the tumor and improved antitumor response. 7HP349 monotherapy had modest effects on anti-programmed death 1-resistant (anti-PD-1-resistant) tumors, whereas combinatorial treatment with anti-cytotoxic …

Frailty Repels The Knife: The Impact Of Frailty Index On Surgical Intervention And Outcomes, Katelyn F Handley, Anil K Sood, Graziela Zibetti Dal Molin, Shannon N Westin, Larissa A Meyer, Bryan Fellman, Pamela T Soliman, Robert L Coleman, Nicole D Fleming

Faculty, Staff and Student Publications

Objective: To assess the impact of frailty in patients with ovarian cancer on surgical procedures and outcomes.

Methods: A retrospective review of patients with stage II-IV ovarian cancer from April 2013 to September 2017 was performed. Patients were triaged by laparoscopy to determine primary resectability. The adjusted modified frailty index score (amFI) was calculated and amFI ≥2 classified as high frailty. Clinical outcomes, progression free survival (PFS) and overall survival (OS) were estimated.

Results: 592 patients met inclusion criteria; amFI of 0, 1 and ≥ 2 was noted in 57%, 29%, and 14%, respectively. Patients with high frailty were less …

Prospecting Cellular Gold Nanoparticle Biomineralization As A Viable Alternative To Prefabricated Gold Nanoparticles, Aaron S Schwartz-Duval, Konstantin V Sokolov

Faculty, Staff and Student Publications

Gold nanoparticles (GNPs) have shown considerable potential in a vast number of biomedical applications. However, currently there are no clinically approved injectable GNP formulations. Conversely, gold salts have been used in the clinic for nearly a century. Further, there is evidence of GNP formation in patients treated with gold salts (i.e., chrysiasis). Recent reports evaluating this phenomenon in human cells and in murine models indicate that the use of gold ions for in situ formation of theranostic GNPs could greatly improve the delivery within dense biological tissues, increase efficiency of intracellular gold uptake, and specificity of GNP formation within cancer …

Cardiovascular Events In Patients Treated With Chimeric Antigen Receptor T-Cell Therapy For Aggressive B-Cell Lymphoma, Raphael E Steiner, Jose Banchs, Efstratios Koutroumpakis, Melody Becnel, Cristina Gutierrez, Paolo Strati, Chelsea C Pinnix, Lei Feng, Gabriela Rondon, Catherine Claussen, Nicolas Palaskas, Kaveh Karimzad, Sairah Ahmed, Sattva S Neelapu, Elizabeth Shpall, Michael Wang, Francisco Vega, Jason Westin, Loretta J Nastoupil, Anita Deswal

Faculty, Staff and Student Publications

Standard of care (SOC) chimeric antigen receptor (CAR) T-cell therapies such as axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are associated with multisystem toxicities. There is limited information available about cardiovascular (CV) events associated with SOC axi-cel or tisa-cel. Patients with CV comorbidities, organ dysfunction, or lower performance status were often excluded in the clinical trials leading to their Food and Drug Adminsitration approval. An improved understanding of CV toxicities in the real-world setting will better inform therapy selection and management of patients receiving these cellular therapies. Here, we retrospectively reviewed the characteristics and outcomes of adult patients with relapsed/refractory large …

A Win Consortium Phase I Study Exploring Avelumab, Palbociclib, And Axitinib In Advanced Non-Small Cell Lung Cancer, Benjamin Solomon, Ana Callejo, Jair Bar, Guy Berchem, Lyudmila Bazhenova, Pierre Saintigny, Fanny Wunder, Jacques Raynaud, Nicolas Girard, J Jack Lee, Raed Sulaiman, Bruce Prouse, Catherine Bresson, Hila Ventura, Shai Magidi, Eitan Rubin, Brandon Young, Amir Onn, Brian Leyland-Jones, Richard L Schilsky, Vladimir Lazar, Enriqueta Felip, Razelle Kurzrock

Faculty, Staff and Student Publications

Background: The Worldwide Innovative Network (WIN) Consortium has developed the Simplified Interventional Mapping System (SIMS) to better define the cancer molecular milieu based on genomics/transcriptomics from tumor and analogous normal tissue biopsies. SPRING is the first trial to assess a SIMS-based tri-therapy regimen in advanced non-small cell lung cancer (NSCLC).

Methods: Patients with advanced NSCLC (no EGFR, ALK, or ROS1 alterations; PD-L1 unrestricted; ≤2 prior therapy lines) received avelumab, axitinib, and palbociclib (3 + 3 dose escalation design).

Results: Fifteen patients were treated (five centers, four countries): six at each of dose levels 1 (DL1) and DL2; three at DL3. …

The 5th Edition Of The World Health Organization Classification Of Haematolymphoid Tumours: Lymphoid Neoplasms, Rita Alaggio, Catalina Amador, Ioannis Anagnostopoulos, Ayoma D Attygalle, Iguaracyra Barreto De Oliveira Araujo, Emilio Berti, Govind Bhagat, Anita Maria Borges, Daniel Boyer, Mariarita Calaminici, Amy Chadburn, John K C Chan, Wah Cheuk, Wee-Joo Chng, John K Choi, Shih-Sung Chuang, Sarah E Coupland, Magdalena Czader, Sandeep S Dave, Daphne De Jong, Ming-Qing Du, Kojo S Elenitoba-Johnson, Judith Ferry, Julia Geyer, Dita Gratzinger, Joan Guitart, Sumeet Gujral, Marian Harris, Christine J Harrison, Sylvia Hartmann, Andreas Hochhaus, Patty M Jansen, Kennosuke Karube, Werner Kempf, Joseph Khoury, Hiroshi Kimura, Wolfram Klapper, Alexandra E Kovach, Shaji Kumar, Alexander J Lazar, Stefano Lazzi, Lorenzo Leoncini, Nelson Leung, Vasiliki Leventaki, Xiao-Qiu Li, Megan S Lim, Wei-Ping Liu, Abner Louissaint, Andrea Marcogliese, L Jeffrey Medeiros, Michael Michal, Roberto N Miranda, Christina Mitteldorf, Santiago Montes-Moreno, William Morice, Valentina Nardi, Kikkeri N Naresh, Yasodha Natkunam, Siok-Bian Ng, Ilske Oschlies, German Ott, Marie Parrens, Melissa Pulitzer, S Vincent Rajkumar, Andrew C Rawstron, Karen Rech, Andreas Rosenwald, Jonathan Said, Clémentine Sarkozy, Shahin Sayed, Caner Saygin, Anna Schuh, William Sewell, Reiner Siebert, Aliyah R Sohani, Reuben Tooze, Alexandra Traverse-Glehen, Francisco Vega, Beatrice Vergier, Ashutosh D Wechalekar, Brent Wood, Luc Xerri, Wenbin Xiao

Faculty, Staff and Student Publications

We herein present an overview of the upcoming 5th edition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the revised 4th edition. These include reorganization of entities by a hierarchical system as is adopted throughout the 5th edition of the WHO classification of tumours of all organ systems, modification of nomenclature for some entities, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities, as …

Functional Genomic Analysis Of Epithelioid Sarcoma Reveals Distinct Proximal And Distal Subtype Biology, Samuel V Rasmussen, Jia Xiang Jin, Lissett R Bickford, Andrew D Woods, Felix Sahm, Kenneth A Crawford, Kiyo Nagamori, Hiroaki Goto, Keila E Torres, Angelo Sidoni, Erin R Rudzinski, Khin Thway, Robin L Jones, Alessio Ciulli, Hollis Wright, Melvin Lathara, Ganapati Srinivasa, Kavya Kannan, Paul H Huang, Thomas G P Grünewald, Noah E Berlow, Charles Keller

Faculty, Staff and Student Publications

Background: Metastatic epithelioid sarcoma (EPS) remains a largely unmet clinical need in children, adolescents and young adults despite the advent of EZH2 inhibitor tazemetostat.

Methods: In order to realise consistently effective drug therapies, a functional genomics approach was used to identify key signalling pathway vulnerabilities in a spectrum of EPS patient samples. EPS biopsies/surgical resections and cell lines were studied by next-generation DNA exome and RNA deep sequencing, then EPS cell cultures were tested against a panel of chemical probes to discover signalling pathway targets with the most significant contributions to EPS tumour cell maintenance.

Results: Other biologically inspired functional …

Leveraging Single-Cell Sequencing To Unravel Intratumour Heterogeneity And Tumour Evolution In Human Cancers, Amy L Bowes, Maxime Tarabichi, Nischalan Pillay, Peter Van Loo

Faculty, Staff and Student Publications

Intratumour heterogeneity (ITH) and tumour evolution are well-documented phenomena in human cancers. While the advent of next-generation sequencing technologies has facilitated the large-scale capture of genomic data, the field of single-cell genomics is nascent but rapidly advancing and generating many new insights into the complex molecular mechanisms of tumour biology. In this review, we provide an overview of current single-cell DNA sequencing technologies, exploring how recent methodological advancements have enumerated new insights into ITH and tumour evolution. Areas highlighted include the potential power of single-cell genome sequencing studies to explore evolutionary dynamics contributing to tumourigenesis through to progression, metastasis, and …

Activating Connexin43 Gap Junctions Primes Adipose Tissue For Therapeutic Intervention, Yi Zhu, Na Li, Mingyang Huang, Xi Chen, Yu A An, Jianping Li, Shangang Zhao, Jan-Bernd Funcke, Jianhong Cao, Zhenyan He, Qingzhang Zhu, Zhuzhen Zhang, Zhao V Wang, Lin Xu, Kevin W Williams, Chien Li, Kevin Grove, Philipp E Scherer

Faculty, Staff and Students Publications

Adipose tissue is a promising target for treating obesity and metabolic diseases. However, pharmacological agents usually fail to effectively engage adipocytes due to their extraordinarily large size and insufficient vascularization, especially in obese subjects. We have previously shown that during cold exposure, connexin43 (Cx43) gap junctions are induced and activated to connect neighboring adipocytes to share limited sympathetic neuronal input amongst multiple cells. We reason the same mechanism may be leveraged to improve the efficacy of various pharmacological agents that target adipose tissue. Using an adipose tissue-specific Cx43 overexpression mouse model, we demonstrate effectiveness in connecting adipocytes to augment metabolic …

High-Throughput Profiling Of Histone Post-Translational Modifications And Chromatin Modifying Proteins By Reverse Phase Protein Array, Xuan Wang, Zhongcheng Shi, Hsin-Yi Lu, Jean J Kim, Wen Bu, Jose A Villalobos, Dimuthu N Perera, Sung Yun Jung, Tao Wang, Sandra L Grimm, Bethany C Taylor, Kimal Rajapakshe, Hyekyung Park, Julia Wulfkuhle, Nicolas L Young, Yi Li, Cristian Coarfa, Dean P Edwards, Shixia Huang

Faculty, Staff and Students Publications

Epigenetic variation plays a significant role in normal development and human diseases including cancer, in part through post-translational modifications (PTMs) of histones. Identification and profiling of changes in histone PTMs, and in proteins regulating PTMs, are crucial to understanding diseases, and for discovery of epigenetic therapeutic agents. In this study, we have adapted and validated an antibody-based reverse phase protein array (RPPA) platform for profiling 20 histone PTMs and expression of 40 proteins that modify histones and other epigenomic regulators. The specificity of the RPPA assay for histone PTMs was validated with synthetic peptides corresponding to histone PTMs and by …

Genotype-To-Phenotype Associations In The Aggressive Variant Prostate Cancer Molecular Profile (Avpc-M) Components, Rama Soundararajan, Paul Viscuse, Patrick Pilie, Jingjing Liu, Souzana Logotheti, Caddie Laberiano Fernández, Daniele Lorenzini, Anh Hoang, Wei Lu, Luisa Maren Solis Soto, Ignacio I Wistuba, Mingchu Xu, Xingzhi Song, Peter D A Shepherd, Nora M Navone, Rebecca S S Tidwell, Guillermina Lozano, Christopher Logothetis, Jianhua Zhang, James P Long, Marcos R Estecio, Vasiliki Tzelepi, Ana M Aparicio

Faculty, Staff and Student Publications

The aggressive variant prostate cancer molecular profile (AVPC-m), composed of combined defects in TP53, RB1 and PTEN, characterizes a subset of prostate cancers linked to androgen indifference and platinum sensitivity. To contribute to the optimization of the AVPC-m assessment for inclusion in prospective clinical trials, we investigated the status of the AVPC-m components in 28 patient tumor-derived xenografts (PDXs) developed at MDACC. We subjected single formalin-fixed, paraffin-embedded (FFPE) blocks from each PDX to immunohistochemistry (IHC), targeted next-generation genomic sequencing (NGS) and Clariom-S Affymetrix human microarray expression profiling. Standard validated IHC assays and a 10% labeling index cutoff resulted in high …

Ewi2 Prevents Egfr From Clustering And Endocytosis To Reduce Tumor Cell Movement And Proliferation, Chenying Fu, Jie Wang, Sandeep Pallikkuth, Yingjun Ding, Junxiong Chen, Jonathan D Wren, Yuchao Yang, Kwong-Kwok Wong, Hiroyasu Kameyama, Muralidharan Jayaraman, Anupama Munshi, Takemi Tanaka, Keith A Lidke, Xin A Zhang

Faculty, Staff and Student Publications

EWI2 is a transmembrane immunoglobulin superfamily (IgSF) protein that physically associates with tetraspanins and integrins. It inhibits cancer cells by influencing the interactions among membrane molecules including the tetraspanins and integrins. The present study revealed that, upon EWI2 silencing or ablation, the elevated movement and proliferation of cancer cells in vitro and increased cancer metastatic potential and malignancy in vivo are associated with (i) increases in clustering, endocytosis, and then activation of EGFR and (ii) enhancement of Erk MAP kinase signaling. These changes in signaling make cancer cells (i) undergo partial epithelial-to-mesenchymal (EMT) for more tumor progression and (ii) proliferate …

Aberrant Dna Hydroxymethylation Reshapes Transcription Factor Binding In Myeloid Neoplasms, Jia Li, Tingting Hong, Yue Wei, Lei Guo, Minjung Lee, Hui Yang, Caleb Class, Yaling Yang, Xiaoqiong Wang, Hua He, Stefan Siwko, M James You, Yubin Zhou, Guillermo Garcia-Manero, Yun Huang

Faculty, Staff and Student Publications

Epigenetic abnormalities in DNA hydroxymethylation (5hmC) have been detected in patients with myeloid neoplasms, suggesting that 5hmC might act as a valuable epigenetic mark to reflect the disease status of myeloid neoplasms. Here, we report systematic genome-wide mapping of the DNA hydroxymethylomes in over 70 patients with myeloid neoplasms. Our integrative analysis leads to the identification of distinct 5hmC signatures that can sensitively discriminate patients from healthy individuals. At the molecular level, we unveiled dynamic 5hmC changes within key transcription factor (e.g., the CEBP family) binding motifs that are essential for hematopoiesis and myeloid lineage specification. 5hmC redistribution was found …

Reflections On Beam Configuration Optimization For Intensity-Modulated Proton Therapy, Wenhua Cao, Humberto Rocha, Radhe Mohan, Gino Lim, Hadis M Goudarzi, Brígida C Ferreira, Joana M Dias

Faculty, Staff and Student Publications

Presumably, intensity-modulated proton radiotherapy (IMPT) is the most powerful form of proton radiotherapy. In the current state of the art, IMPT beam configurations (i.e. the number of beams and their directions) are, in general, chosen subjectively based on prior experience and practicality. Beam configuration optimization (BCO) for IMPT could, in theory, significantly enhance IMPT's therapeutic potential. However, BCO is complex and highly computer resource-intensive. Some algorithms for BCO have been developed for intensity-modulated photon therapy (IMRT). They are rarely used clinically mainly because the large number of beams typically employed in IMRT renders BCO essentially unnecessary. Moreover, in the newer …

Occult Polyclonality Of Preclinical Pancreatic Cancer Models Drives In Vitro Evolution, Maria E Monberg, Heather Geiger, Jaewon J Lee, Roshan Sharma, Alexander Semaan, Vincent Bernard, Justin Wong, Fang Wang, Shaoheng Liang, Daniel B Swartzlander, Bret M Stephens, Matthew H G Katz, Ken Chen, Nicolas Robine, Paola A Guerrero, Anirban Maitra

Faculty, Staff and Student Publications

Heterogeneity is a hallmark of cancer. The advent of single-cell technologies has helped uncover heterogeneity in a high-throughput manner in different cancers across varied contexts. Here we apply single-cell sequencing technologies to reveal inherent heterogeneity in assumptively monoclonal pancreatic cancer (PDAC) cell lines and patient-derived organoids (PDOs). Our findings reveal a high degree of both genomic and transcriptomic polyclonality in monolayer PDAC cell lines, custodial variation induced by growing apparently identical cell lines in different laboratories, and transcriptomic shifts in transitioning from 2D to 3D spheroid growth models. Our findings also call into question the validity of widely available immortalized, …

The Three Two-Pore Channel Subtypes From Rabbit Exhibit Distinct Sensitivity To Phosphoinositides, Voltage, And Extracytosolic Ph, Xinghua Feng, Jian Xiong, Weijie Cai, Jin-Bin Tian, Michael X Zhu

Faculty, Staff and Student Publications

Two pore channels (TPCs) are implicated in vesicle trafficking, virus infection, and autophagy regulation. As Na+- or Ca2+-permeable channels, TPCs have been reported to be activated by NAADP, PI(3,5)P2, and/or high voltage. However, a comparative study on the function and regulation of the three mammalian TPC subtypes is currently lacking. Here, we used the electrophysiological recording of enlarged endolysosome vacuoles, inside-out and outside-out membrane patches to examine the three TPCs of rabbit (Oryctolagus cuniculus, or Oc) heterologously expressed in HEK293 cells. While PI(3,5)P2 evoked Na+ currents with a potency order of OcTPC1 > OcTPC3 > OcTPC2, only OcTPC2 displayed a strict dependence …

Hematologic Complications Of Immune Checkpoint Inhibitors, Michael H Kroll, Cristhiam Rojas-Hernandez, Cassian Yee

Faculty, Staff and Student Publications

Immune checkpoint inhibitors are a class of antineoplastic therapies that unleash immune cells to kill malignant cells. There are currently 7 medications that have been approved by the US Food and Drug Administration for the treatment of 14 solid tumors and 2 hematologic malignancies. These medications commonly cause immune-related adverse effects as a result of overactive T lymphocytes, autoantibody production, and/or cytokine dysregulation. Hematologic toxicities are rare and of uncertain mechanism, and therefore management is often based on experiences with familiar conditions involving these perturbed immune responses, such as autoimmune hemolytic anemia, immune thrombocytopenia, and idiopathic aplastic anemia. Management is …

Effect Of Neoadjuvant Chemotherapy On Intraoperative Core Temperature In Patients With Breast Cancer: A Retrospective Cohort Study, Daniel B Zamler, Takashi Shingu, Laura M Kahn, Kristin Huntoon, Cynthia Kassab, Martina Ott, Katarzyna Tomczak, Jintan Liu, Yating Li, Ivy Lai, Rocio Zorilla-Veloz, Cassian Yee, Kunal Rai, Betty Ys Kim, Stephanie S Watowich, Amy B Heimberger, Giulio F Draetta, Jian Hu

Faculty, Staff and Student Publications

Novel therapeutic strategies targeting glioblastoma (GBM) often fail in the clinic, partly because preclinical models in which hypotheses are being tested do not recapitulate human disease. To address this challenge, we took advantage of our previously developed spontaneous Qk/Trp53/Pten (QPP) triple-knockout model of human GBM, comparing the immune microenvironment of QPP mice with that of patient-derived tumors to determine whether this model provides opportunity for gaining insights into tumor physiopathology and preclinical evaluation of therapeutic agents. Immune profiling analyses and single-cell sequencing of implanted and spontaneous tumors from QPP mice and from patients with glioma revealed intratumoral immune components that …

Immune Landscape Of A Genetically Engineered Murine Model Of Glioma Compared With Human Glioma, Daniel B Zamler, Takashi Shingu, Laura M Kahn, Kristin Huntoon, Cynthia Kassab, Martina Ott, Katarzyna Tomczak, Jintan Liu, Yating Li, Ivy Lai, Rocio Zorilla-Veloz, Cassian Yee, Kunal Rai, Betty Ys Kim, Stephanie S Watowich, Amy B Heimberger, Giulio F Draetta, Jian Hu

Faculty, Staff and Student Publications

Novel therapeutic strategies targeting glioblastoma (GBM) often fail in the clinic, partly because preclinical models in which hypotheses are being tested do not recapitulate human disease. To address this challenge, we took advantage of our previously developed spontaneous Qk/Trp53/Pten (QPP) triple-knockout model of human GBM, comparing the immune microenvironment of QPP mice with that of patient-derived tumors to determine whether this model provides opportunity for gaining insights into tumor physiopathology and preclinical evaluation of therapeutic agents. Immune profiling analyses and single-cell sequencing of implanted and spontaneous tumors from QPP mice and from patients with glioma revealed intratumoral immune components that …

Integrated Screens Uncover A Cell Surface Tumor Suppressor Gene Kirrel Involved In Hippo Pathway, Chao Wang, Xu Feng, Dan Su, Zhen Chen, Shimin Wang, Mengfan Tang, Min Huang, Litong Nie, Huimin Zhang, Siting Li, Ling Yin, Randy L Johnson, Traver Hart, Junjie Chen

Faculty, Staff and Student Publications

Cell surface proteins play essential roles in various biological processes and are highly related to cancer development. They also serve as important markers for cell identity and targets for pharmacological intervention. Despite their great potentials in biomedical research, comprehensive functional analysis of cell surface proteins remains scarce. Here, with a de novo designed library targeting cell surface proteins, we performed in vivo CRISPR screens to evaluate the effects of cell surface proteins on tumor survival and proliferation. We found that

Promoting Cancer Health Equity: A Qualitative Study Of Mentee And Mentor Perspectives Of A Training Program For Underrepresented Scholars In Cancer Health Disparities, Anastasia Rogova, Isabel Martinez Leal, Maggie Britton, Shine Chang, Kamisha H Escoto, Kayce D Solari Williams, Crystal Roberson, Lorna H Mcneill, Lorraine R Reitzel

Faculty, Staff and Student Publications

Racial and ethnic minorities, and women, experience stark disparities in cancer risk behaviors and mortality rates, yet often remain underrepresented in scientific research positions. We conducted an exploratory, qualitative study to examine the value of mentored research experience as part of an NCI-funded research training program designed to increase the representation of minority and women scientists in cancer disparities research. Using individual interviews, we explored 16 mentees' and 7 mentors' program experiences and perspectives to identify the most effective strategies to build strong mentoring relationships that could ultimately contribute to increased representation in health disparities research. Two expert analysts employed …

Directed Evolution Of Pd-L1-Targeted Affibodies By Mrna Display, Brian J Grindel, Brian J Engel, Justin N Ong, Anupallavi Srinivasamani, Xiaowen Liang, Niki M Zacharias, Robert C Bast, Michael A Curran, Terry T Takahashi, Richard W Roberts, Steven W Millward

Faculty, Staff and Student Publications

Therapeutic monoclonal antibodies directed against PD-L1 (e.g., atezolizumab) disrupt PD-L1:PD-1 signaling and reactivate exhausted cytotoxic T-cells in the tumor compartment. Although anti-PD-L1 antibodies are successful as immune checkpoint inhibitor (ICI) therapeutics, there is still a pressing need to develop high-affinity, low-molecular-weight ligands for molecular imaging and diagnostic applications. Affibodies are small polypeptides (∼60 amino acids) that provide a stable molecular scaffold from which to evolve high-affinity ligands. Despite its proven utility in the development of imaging probes, this scaffold has never been optimized for use in mRNA display, a powerful

Inflammatory Breast Cancer: The Cytokinome Of Post-Mastectomy Wound Fluid Augments Proliferation, Invasion, And Stem Cell Markers, Alshaimaa Tarek, Shrouk Khalaf El-Sayed, Wendy A Woodward, Mohamed El-Shinawi, Jon Mark Hirshon, Mona Mostafa Mohamed

Faculty, Staff and Student Publications

Inflammatory breast cancer (IBC) is an aggressive phenotype with a high recurrence and low survival rate. Approximately 90% of local breast cancer recurrences occur adjacent to the same quadrant as the initial cancer, implying that tumor recurrence may be caused by residual cancer cells and/or quiescent cancer stem cells (CSCs) in the tumor. We hypothesized that wound fluid (WF) collected after modified radical mastectomy (MRM) may activate cancer cells and CSCs, promoting epithelial mesenchymal transition (EMT) and invasion. Therefore, we characterized the cytokinome of WF drained from post-MRM cavities of non-IBC and IBC patients. The WF of IBC patients showed …

Chemotherapy Coupled To Macrophage Inhibition Induces T-Cell And B-Cell Infiltration And Durable Regression In Triple-Negative Breast Cancer, Swarnima Singh, Nigel Lee, Diego A Pedroza, Igor L Bado, Clark Hamor, Licheng Zhang, Sergio Aguirre, Jingyuan Hu, Yichao Shen, Yitian Xu, Yang Gao, Na Zhao, Shu-Hsia Chen, Ying-Wooi Wan, Zhandong Liu, Jeffrey T Chang, Daniel Hollern, Charles M Perou, Xiang H F Zhang, Jeffrey M Rosen

Duncan NRI Faculty and Staff Publications

Immunosuppressive elements within the tumor microenvironment, such as tumor-associated macrophages (TAM), can present a barrier to successful anti-tumor responses by cytolytic T cells. Here we employed preclinical syngeneic p53 null mouse models of triple-negative breast cancer (TNBC) to develop a treatment regimen that harnessed the immunostimulatory effects of low-dose cyclophosphamide coupled with the pharmacologic inhibition of TAMs using either a small molecule CSF1R inhibitor or an anti-CSF1R antibody. This therapeutic combination was effective in treating several highly aggressive TNBC murine mammary tumor and lung metastasis models. Single cell RNA sequencing characterized tumor-infiltrating lymphocytes (TIL) including helper T cells and antigen-presenting …

Neoadjuvant Immunotherapy Across Cancers: Meeting Report From The Immunotherapy Bridge-December 1st–2nd, 2021, Elizabeth M Burton, Rodabe N Amaria, Tina Cascone, Myriam Chalabi, Neil D Gross, Elizabeth A Mittendorf, Richard A Scolyer, Padmanee Sharma, Paolo A Ascierto

Faculty, Staff and Student Publications

After the success of immunotherapy in the treatment of advanced metastatic cancer, further evaluation in earlier settings, including high-risk, surgically-resectable disease is underway. Potential benefits of a neoadjuvant immunotherapeutic approach include presurgical tumor shrinkage, reduced surgical morbidity, early eradication of micrometastases and prevention of distant disease, and greater antigen-specific T cell response. For some cancers, pathologic response has been established as a surrogate measure for long-term outcomes, therefore offering the ability for early and objective assessment of treatment efficacy and the potential to inform and personalize adjuvant treatment clinical decision-making. Leveraging the neoadjuvant treatment setting offers the ability to deeply …

Real-World Use Of Palbociclib Monotherapy In Retroperitoneal Liposarcomas At A Large Volume Sarcoma Center, Elise F Nassif, Brandon Cope, Raymond Traweek, Russell G Witt, Derek J Erstad, Christopher P Scally, Prapassorn Thirasastr, Maria Alejandra Zarzour, Joseph Ludwig, Robert Benjamin, Andrew J Bishop, B Ashleigh Guadagnolo, Davis Ingram, Khalida Wani, Wei-Lien Wang, Alexander J Lazar, Keila E Torres, Kelly K Hunt, Barry W Feig, Christina L Roland, Neeta Somaiah, Emily Z Keung

Faculty, Staff and Student Publications

Palbociclib has been evaluated in early phase trials for well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) patients, with reported median progression-free survival (PFS) of 18 weeks. Here, we report on real-world use and surgical outcomes associated with palbociclib treatment. We retrospectively reviewed 61 consecutive patients with retroperitoneal WDLPS (n = 14) or DDLPS (n = 47) treated with palbociclib monotherapy between 1 March 2016 and 28 February 2021 at The University of Texas MD Anderson Cancer Center. At palbociclib initiation, median age was 64 (interquartile range [IQR] 56-72). In WDLPS and DDLPS cohorts, the median number of prior systemic treatments …

Sirpα+ Macrophages Are Increased In Patients With Fl Who Progress Or Relapse After Frontline Lenalidomide And Rituximab, Mario L Marques-Piubelli, Edwin R Parra, Lei Feng, Luisa Solis Soto, Mariana Gallardo, Sushanth Gouni, Felipe Samaniego, Mansoor Noorani, Fredrick B Hagemeister, Jason R Westin, Hun Ju Lee, Maria A Rodriguez, Sattva S Neelapu, Jillian R Gunther, Nathan H Fowler, Christopher R Flowers, Ignacio I Wistuba, Loretta J Nastoupil, Francisco Vega, Paolo Strati

Faculty, Staff and Student Publications

Limited data exist regarding the outcome of patients with follicular lymphoma (FL) who relapse or progress after frontline lenalidomide and rituximab (R2). Moreover, mechanisms of resistance to R2 in FL remain unclear, with increased protumoral macrophages suspected as a major contributory culprit to this phenomenon. This retrospective study analyzed the outcome of patients with advanced-stage FL grade 1 to 3A who relapsed or progressed after frontline R2. A multiplex immunofluorescence macrophage panel, including CD47, CD14, CD68, CD115 (also known as colony-stimulating factor 1 receptor [CSF1R]), CD163, CD172a (also known as signal regulatory protein α [SIRPα]), and CD274 (also known as …

Genome-Wide Crispr Screens Using Isogenic Cells Reveal Vulnerabilities Conferred By Loss Of Tumor Suppressors, Rodney Cheng-En Hsieh, Sunil Krishnan, Ren-Chin Wu, Akash R Boda, Arthur Liu, Michelle Winkler, Wen-Hao Hsu, Steven Hsesheng Lin, Mien-Chie Hung, Li-Chuan Chan, Krithikaa Rajkumar Bhanu, Anupallavi Srinivasamani, Ricardo Alexandre De Azevedo, Yung-Chih Chou, Ronald A Depinho, Matthew Gubin, Eduardo Vilar, Chao Hsien Chen, Ravaen Slay, Priyamvada Jayaprakash, Shweta Mahendra Hegde, Genevieve Hartley, Spencer T Lea, Rishika Prasad, Brittany Morrow, Coline Agnes Couillault, Madeline Steiner, Chun-Chieh Wang, Bhanu Prasad Venkatesulu, Cullen Taniguchi, Yon Son Betty Kim, Junjie Chen, Nils-Petter Rudqvist, Michael A Curran

Faculty, Staff and Student Publications

Radiotherapy (RT) of colorectal cancer (CRC) can prime adaptive immunity against tumor-associated antigen (TAA)-expressing CRC cells systemically. However, abscopal tumor remissions are extremely rare, and the postirradiation immune escape mechanisms in CRC remain elusive. Here, we found that irradiated CRC cells used ATR-mediated DNA repair signaling pathway to up-regulate both CD47 and PD-L1, which through engagement of SIRPα and PD-1, respectively, prevented phagocytosis by antigen-presenting cells and thereby limited TAA cross-presentation and innate immune activation. This postirradiation CD47 and PD-L1 up-regulation was observed across various human solid tumor cells. Concordantly, rectal cancer patients with poor responses to neoadjuvant RT exhibited …

Risk Of Peritoneal Carcinomatosis After Risk-Reducing Salpingo-Oophorectomy: A Systematic Review And Individual Patient Data Meta-Analysis, Miranda P Steenbeek, Majke H D Van Bommel, Johan Bulten, Julia A Hulsmann, Joep Bogaerts, Christine Garcia, Han T Cun, Karen H Lu, Heleen J Van Beekhuizen, Lucas Minig, Katja N Gaarenstroom, Marielle Nobbenhuis, Mateja Krajc, Vilius Rudaitis, Barbara M Norquist, Elizabeth M Swisher, Marian J E Mourits, Leon F A G Massuger, Nicoline Hoogerbrugge, Rosella P M G Hermens, Joanna Inthout, Joanne A De Hullu

Faculty, Staff and Student Publications

Purpose: After risk-reducing salpingo-oophorectomy (RRSO), BRCA1/2 pathogenic variant (PV) carriers have a residual risk to develop peritoneal carcinomatosis (PC). The etiology of PC is not yet clarified, but may be related to serous tubal intraepithelial carcinoma (STIC), the postulated origin for high-grade serous cancer. In this systematic review and individual patient data meta-analysis, we investigate the risk of PC in women with and without STIC at RRSO.

Methods: Unpublished data from three centers were supplemented by studies identified in a systematic review of EMBASE, MEDLINE, and the Cochrane library describing women with a BRCA-PV with and without …

Atr-Mediated Cd47 And Pd-L1 Up-Regulation Restricts Radiotherapy-Induced Immune Prming And Abscopal Responses In Colorectal Cancer, Rodney Cheng-En Hsieh, Sunil Krishnan, Ren-Chin Wu, Akash R Boda, Arthur Liu, Michelle Winkler, Wen-Hao Hsu, Steven Hsesheng Lin, Mien-Chie Hung, Li-Chuan Chan, Krithikaa Rajkumar Bhanu, Anupallavi Srinivasamani, Ricardo Alexandre De Azevedo, Yung-Chih Chou, Ronald A Depinho, Matthew Gubin, Eduardo Vilar, Chao Hsien Chen, Ravaen Slay, Priyamvada Jayaprakash, Shweta Mahendra Hegde, Genevieve Hartley, Spencer T Lea, Rishika Prasad, Brittany Morrow, Coline Agnes Couillault, Madeline Steiner, Chun-Chieh Wang, Bhanu Prasad Venkatesulu, Cullen Taniguchi, Yon Son Betty Kim, Junjie Chen, Nils-Petter Rudqvist, Michael A Curran

Faculty, Staff and Student Publications

Radiotherapy (RT) of colorectal cancer (CRC) can prime adaptive immunity against tumor-associated antigen (TAA)-expressing CRC cells systemically. However, abscopal tumor remissions are extremely rare, and the postirradiation immune escape mechanisms in CRC remain elusive. Here, we found that irradiated CRC cells used ATR-mediated DNA repair signaling pathway to up-regulate both CD47 and PD-L1, which through engagement of SIRPα and PD-1, respectively, prevented phagocytosis by antigen-presenting cells and thereby limited TAA cross-presentation and innate immune activation. This postirradiation CD47 and PD-L1 up-regulation was observed across various human solid tumor cells. Concordantly, rectal cancer patients with poor responses to neoadjuvant RT exhibited …