Medical Genetics Commons^™

Genome-Wide Crispr Screens Identify Critical Targets To Enhance Car-Nk Cell Antitumor Potency, Alexander Biederstädt, Rafet Basar, Jeong-Min Park, Nadima Uprety, Rejeena Shrestha, Francia Reyes Silva, Merve Dede, John Watts, Sunil Acharya, Donghai Xiong, Bin Liu, May Daher, Hind Rafei, Pinaki Banerjee, Ping Li, Sanjida Islam, Huihui Fan, Mayra Shanley, Jingling Jin, Bijender Kumar, Vernikka Woods, Paul Lin, Silvia Tiberti, Ana Karen Nunez Cortes, Xin Ru Jiang, Inci Biederstädt, Patrick Zhang, Ye Li, Seema Rawal, Enli Liu, Luis Muniz-Feliciano, Gary M Deyter, Elizabeth J Shpall, Natalie Wall Fowlkes, Ken Chen, Katayoun Rezvani

Faculty, Staff and Student Publications

Adoptive cell therapy using engineered natural killer (NK) cells is a promising approach for cancer treatment, with targeted gene editing offering the potential to further enhance their therapeutic efficacy. However, the spectrum of actionable genetic targets to overcome tumor and microenvironment-mediated immunosuppression remains largely unexplored. We performed multiple genome-wide CRISPR screens in primary human NK cells and identified critical checkpoints regulating resistance to immunosuppressive pressures. Ablation of MED12, ARIH2, and CCNC significantly improved NK cell antitumor activity against multiple treatment-refractory human cancers in vitro and in vivo. CRISPR editing augmented both innate and CAR-mediated NK cell function, associated with enhanced …

Development Of A Targeted Bioprotac Degrader Selective For Misfolded Sod1, Christen G Chisholm, Rachael Bartlett, Mikayla L Brown, Emma-Jayne Proctor, Natalie E Farrawell, Jody Gorman, Fabien Delerue, Lars M Ittner, Kara L Vine-Perrow, Heath Ecroyd, Neil R Cashman, Darren N Saunders, Luke Mcalary, Jeremy S Lum, Justin J Yerbury

Faculty, Staff and Student Publications

The accumulation of misfolded proteins underlies a broad range of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Due to their dynamic nature, these misfolded proteins have proven challenging to target therapeutically. Here, we specifically target misfolded disease variants of the ALS-associated protein superoxide dismutase 1 (SOD1), using a biological proteolysis targeting chimera (BioPROTAC) composed of a SOD1-specific intrabody and an E3 ubiquitin ligase. Screening of intrabodies and E3 ligases for optimal BioPROTAC construction reveals a candidate capable of degrading multiple disease variants of SOD1, preventing their aggregation in cells. Using CRISPR/Cas9 technology to develop a BioPROTAC transgenic mouse line, we …

Distinguishing Syndromic And Nonsyndromic Cleft Palate Through Analysis Of Protein-Altering De Novo Variants In 818 Trios, Kelsey R Robinson, Sarah W Curtis, Justin E Paschall, Wasiu Lanre Adeyemo, Terri H Beaty, Azeez Butali, Carmen J Buxó, David J Cutler, Michael P Epstein, Lord J J Gowans, Jacqueline T Hecht, Gary M Shaw, Lina Moreno Uribe, Jeffrey C Murray, Harrison Brand, Seth M Weinberg, Mary L Marazita, Kimberly F Doheny, Elizabeth J Leslie-Clarkson

Faculty, Staff and Student Publications

De novo variants (DNs) are sporadically occurring variants found in an offspring but absent in both parents. DNs most commonly arise in the germline and are not under selective pressure; therefore, they may be enriched for disease-causing alleles. In fact, DNs have been implicated in multiple rare genetic disorders. Cleft palate (CP) is a craniofacial congenital anomaly occurring in ∼1 in 1,700 live births. Genome-wide association studies have found fewer than a dozen CP-specific loci, while exome and targeted sequencing studies in family-based and case-control cohorts often lack statistical power to conclusively identify causal variants. We therefore hypothesized that CP …

Compadre: Combined Pedigree-Aware Distant Relatedness Estimation For Improved Pedigree Reconstruction, Grahame F Evans, James T Baker, Lauren E Petty, Alexander S Petty, Hannah G Polikowsky, Ryan J Bohlender, Hung-Hsin Chen, Che-Yu Chou, Kathryn Z Viljoen, Janet M Beilby, Shelly Jo Kraft, Wanying Zhu, Joshua M Landman, Autumn R Morrow, Dayi Bian, Alyssa C Scartozzi, Chad D Huff, Jennifer E Below

Faculty, Staff and Student Publications

Designing powerful and unbiased genomic studies requires accurate assessment of familial relatedness even when this information is not captured from participants. Characterization of pairwise degrees of relatedness from participants' genetic data enables reconstruction of pedigrees, and several pedigree reconstruction tools have emerged in the last decade. However, limitations of these tools include high computational burden in large datasets, reliance on external information, reduced accuracy in admixed populations, and most notably, an inability to accurately reconstruct pedigrees when only a subset of family members is represented in the genetic data. To improve pedigree reconstruction in large-scale data and in pedigrees with …

Distinct Tumor-Associated Macrophage Signatures Shape The Immune Microenvironment And Patient Prognosis In Renal Cell Carcinoma, Youngsoo Han, Aidan Shen, Cheng-Chi Chao, Lucas Yeung, Aliesha Garrett, Jianming Zeng, Satoru Kawakita, Jesse Wang, Zhaohui Wang, Alireza Hassani, Xiling Shen, Chongming Jiang

Faculty, Staff and Student Publications

Renal cell carcinoma (RCC) accounts for 90% of adult renal cancer cases and is characterized by significant heterogeneity within its tumor microenvironment. This study tests the hypothesis that tumor-associated macrophages (TAMs) influence RCC progression and patient response to treatment by investigating the prognostic implications of TAM signatures. Utilizing independent single-cell RNA sequencing data from RCC patients, we developed eight distinct TAM signatures reflective of TAM presence. A LASSO Cox regression model was constructed to predict survival outcomes, evaluated using the TCGA dataset, and validated across independent RCC cohorts. Model performance was assessed through Kaplan-Meier survival plots, receiver operating characteristic (ROC) …

Menin Inhibitor Ds-1594b Drives Differentiation And Induces Synergistic Lethality In Combination With Venetoclax In Acute Myeloid Leukemia Cells With Rearranged Mixed-Lineage Leukemia And Mutated Nucleophosmin-1, Valerio Ciaurro, Vassilena Sharlandjieva, Anna Skwarska, Catherine Chahrour, Natalia Baran, Zhihong Zeng, Cassandra Ramage, Naval Daver, Bing Z Carter, Sovira Chaundhry, Palaniraja Thandapani, Maria Paola Martelli, Thomas A Milne, Marina Konopleva

Faculty, Staff and Student Publications

Mixed-lineage leukemia (MLL) rearrangements and Nucleophosmin-1 (NPM1) mutations are associated with acute leukemias whose pathogenesis is critically influenced by protein-protein interactions between menin and MLL. We hypothesized that targeting the menin-MLL interaction using DS-1594b and blocking the antiapoptotic BCL-2 protein using venetoclax may promote differentiation and enhance eradication of MLL-rearranged and NPM1-mutated leukemias models. We treated acute myeloid leukemia (AML) cell lines with MLL rearrangements, NPM1 mutations, other leukemias and primary samples from AML patients with venetoclax alone, DS- 1594b alone, and their combination. We measured proliferation, viability, apoptosis, and differentiation using a variety of cellular assays, Western blotting, and …

Mutational Landscape And Clinical Impact Of Spen Mutations In Patients With Chronic Lymphocytic Leukemia, Priyatharsini Nirmalanantham, Andrés E Quesada, Anindita Ghosh, Pei Lin, Chi Y Ok, Richard K Yang, Hong Fang, Sofia Garces, Rashmi Kanagal-Shamanna, Sanam Loghavi, Mark J Routbort, Cameron Cheng Yin, Wang Wei, Sarah Pasyar, Roland Bassett, Siba El Hussein, Nitin Jain, Jan Burger, William G Wierda, Sa Wang, Carlos Bueso-Ramos, Keyur P Patel, Leonard Jeffrey Medeiros, Fatima Zahra Jelloul

Faculty, Staff and Student Publications

Background/objectives: NOTCH1 is frequently mutated in chronic lymphocytic leukemia (CLL) and is a marker of poor prognosis. In addition to NOTCH1, mutations in the NOTCH1 regulatory pathway including SPEN have been described in a limited number of CLL cases and others have suggested that these mutations are also associated with adverse patient outcomes Methods: In this study, 1617 CLL cases were assessed using targeted sequencing and a 29-gene panel and the results were correlated with prognosis.

Results: SPEN mutations were detected in 48 (2.9%) CLL patients: 92.4% were deleterious (frameshift or truncating nonsense mutations) and the remaining (7.6%) were …

Incidence And Risk Factors For Pneumonitis Due To Trastuzumab Deruxtecan In Metastatic Breast Cancer: A Retrospective Cohort Study, Maria Azhar, Felipe Soto, Amber Su, Norma Alicia Vazquez Gonzalez, Kevin Bernal Medina, Alejandro Lizarraga Madrigal, Cesar Chavez Duran, Carlos Ignacio Rodriguez Reyna, Colin Chan, Girish S Shroff, Roland L Bassett, Sarah Pasyar, David Zhang, Vickie R Shannon, Mehmet Altan, Melissa P Mitchell, Funda Meric-Bernstam, Jason Mouabbi, Rashmi K Murthy, Saadia A Faiz, Lara Bashoura, Bora Lim, Ajay Sheshadri

Faculty, Staff and Student Publications

Background: Fam-trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) that targets human epidermal growth factor receptor 2 (HER2) and delivers a topoisomerase inhibitor payload. T-DXd has been effectively used to treat metastatic breast cancer but causes pneumonitis in 10–15% of cases. Risk factors associated with T-DXd pneumonitis are not well described.

Research question: What are the major clinical risk factors for T-DXd pneumonitis?

Study design and methods: We conducted a retrospective study of women with metastatic breast cancer at our institution treated with T-DXd as standard of care between 2020 and 2024. We collected clinical data, including demographics, relevant review …

Integrating Pathogenic Variants, Polygenic Risk Score, And Family History For Prostate Cancer Risk Estimation In Men Of African Ancestry, Fei Chen, Xin Sheng, Anqi Wang, Yili Xu, Raymond Hughley, Wei Xiong, Loreall Pooler, Peggy Wan, Susan M Gundell, Godfrey Kigozi, Gertrude Nakigozi, Fred Nalugoda, Joseph Kagaayi, Grace Nalwoga Kigozi, Stephen Mugamba, Emmanuel Kyasanku, James Nkale, Vitalis Ofumbi Olwa, Alexander Lubwama, Alex Daama, Resty Nakajugo, Ben Adusei, Mohamed Jalloh, Serigne Magueye Gueye, Andrew A Adjei, James Mensah, Pedro W Fernandez, Akindele Olupelumi Adebiyi, J Olufemi Ogunbiyi, Oseremen Inokhoife Aisuodionoe-Shadrach, Lindsay Petersen, Wenlong Carl Chen, Jo Mcbride, Jeannette T Bensen, James L Mohler, Jack A Taylor, Caroline Andrews, Mbaaga Kigongo, Amanya Colline, Vicky Kiddu, Juliet Namugambe, Shallot Owamaani, Kuteesa Job, Benon Joseph Masaba, Frank Asiimwe, Proscovia Muwanga, Joy Namulondo, Florence Nagawa, Charity Kayiraba, Martin Ogwang, Ronald Okidi, David Oweka, Elio Kitara, James Obonyo, Daniel Lajul, Paul Matovu, Precious Arinda Muheki, Johnson Natumanya, Emmanuel Agaba, Emmanuel Aculokin, Amos Twongyeirwe, George Mutema, Denis Bitamazire, Eboneé N Butler, Sue Ann Ingles, Benjamin A Rybicki, Janet L Stanford, Wei Zheng, Sonja I Berndt, Stephen J Chanock, Chad D Huff, Joseph Lachance, Luc Multigner, Burcu F Darst, Timothy R Rebbeck, Laurent Brureau, Stephen Watya, David V Conti, Christopher A Haiman

Faculty, Staff and Student Publications

BACKGROUND AND OBJECTIVE: The impact of germline pathogenic variants (PVs) in cancer predisposition genes on risk of prostate cancer (PCa) remains understudied in large populations of African ancestry. This study aims to characterize the range of genetic risk of PCa and aggressive disease phenotypes in men of African ancestry.

METHODS: We analyzed 7176 PCa cases and 4873 controls from seven countries across North America and Africa to assess the association between PVs in 37 cancer predisposition genes and the risk of overall, aggressive, and metastatic PCa. Genes significantly associated with PCa risk were used to estimate lifetime absolute risk based …

Cofilin Inhibition Ameliorates Piezo2 And Ampa Dysfunction In A Mouse Model Of Angelman Syndrome, Luis O Romero, Manisha Bade, Elisa Carrillo, Sonia Paz-López, Syed A M Hasan, William James Antonisamy, Vasanthi Jayaraman, Zahoor A Shah, Valeria Vásquez, Julio F Cordero-Morales

Faculty, Staff and Student Publications

Angelman syndrome (AS) is a neurogenetic disorder characterized by motor coordination and cognitive deficits. In AS, hippocampal neurons show reduced filamentous (F-)actin, a decrease we also reported in dorsal root ganglia (DRG) neurons, along with impaired mechanosensitive ion channel activity. Currently, there are no pharmacological targets to prevent the decrease of F-actin in AS. Here, we utilize a first-in-class selective cofilin inhibitor (SZ-3) to restore PIEZO2 function in DRG neurons and glutamate-evoked currents in hippocampal neurons from AS mice. Using atomic force microscopy, we demonstrate that inhibiting cofilin, an actin-severing protein, with SZ-3 increases cellular stiffness by stabilizing the actin …

Targeting Gd2 With Naxitamab Overcomes Gd3 Synthase-Driven Immune Suppression In Triple-Negative Breast Cancer, Vivek Anand, Bolutyfe Oderinde, Maryam Siddiqui, Anudishi Tyagi, Jenny Borgman, Chong Wu, Michael Andreeff, V Lokesh Battula

Faculty, Staff and Student Publications

Gangliosides are acidic glycosphingolipids involved in cell-adhesion, signal-transduction and tumor progression. GD3 synthase (GD3S/ST8SIA1), a key enzyme in ganglioside biosynthesis, is upregulated in many cancers, including GD2+ breast cancer stem-like cells (BCSCs) in triple-negative breast cancer (TNBC). Here, we demonstrated the immunomodulatory role of GD3S and identified a fully humanized anti-GD2 antibody, naxitamab, as a therapeutic tool to target GD3S/GD2+ breast tumors. GD3S expression correlates with immune-checkpoint activation and reduced immune infiltration. Ectopic overexpression of GD3S suppressed macrophage-mediated phagocytosis and NK or T cell-induced cell death in BC cells. Lipidomic analysis identified GD2 as the major effector ganglioside …

Prospective Phase Ii Clinical Trial Of Molecular Glioblastoma (Historical Grade 2 And 3 Idh Wildtype Gliomas) Preliminary Novel Exploratory Analyses: Treatment Intensification, Margin Reduction And Epigenetic Stratified Outcomes With Radiation Therapy And Chemotherapy, Debra Nana Yeboa, Benjamin T Whitfield, Ruitao Lin, Chinenye Lynette Ejezie, Todd A Swanson, Thomas H Beckham, Chenyang Wang, Brian De, Subha Perni, Martin C Tom, Jing Li, Susan L Mcgovern, Rebecca Harrison, Nazanin K Majd, Vinay K Puduvalli, Ashley E Aaroe, Monica Loghin, Barbara J O'Brien, Anuj D Patel, Chirag B Patel, Jeffrey S Wefel, Ceylan Altintas Taslicay, Maria Gule-Monroe, Arnold C Paulino, Mary Frances Mcaleer, David R Grosshans, Amol J Ghia, Wen Jiang, Caroline Chung, Moshe Maor, Cheng-Han Yang, Maria A Gubbiotti, Carlos Kamiya-Matsuoka, Leomar Y Ballester, Shiao-Pei Weathers, Jason T Huse

Faculty, Staff and Student Publications

Purpose: Molecular glioblastoma (molGBM) is a variant lacking the full histopathological profile of glioblastoma. We report a trial aimed at addressing the optimal management of this newly recognized rarer form of glioma.

Methods: In this phase II study, molGBM patients were treated with radiation to a dose of 60Gy to the gross tumor volume (GTV) only, and a single smaller margin potentially as low as 1cm to the clinical tumor volume (CTV). As the trial is ongoing, we report on important exploratory biomarker findings correlating with median overall survival (mOS). Analysis included Kaplan-Meier and univariable/multivariable cox proportional hazard models. Available …

Effects Of Combining Traditional East Asian And Conventional Western Medicine On Acute Stroke Outcomes, Dong-Seok Gwak, Jong-Sik Lee, Dawid Schellingerhout, Jinyong Chung, Hyerin Oh, Sang-Wuk Jeong, Ji Sung Lee, Hee-Joon Bae, Mikyung Kim, Dong-Jun Choi, Dong-Eog Kim

Faculty, Staff and Student Publications

Background: Traditional East Asian medicine (TM) is widely used in Korea and other East Asian countries. However, the effects of TM treatment on acute ischemic stroke (AIS) outcomes remain unclear, as previous studies lacked a sufficient sample size, a consecutive series design, or a prospective outcome capture approach. We aimed to investigate whether combining TM with conventional Western medicine (CM) treatments (C+TM) leads to better outcomes after AIS, relative to CM treatment alone.

Methods: We retrospectively analyzed 2157 consecutive patients with AIS from a prospectively collected registry (2011-2021) at our center and compared the CM and C+TM groups in terms …

Pregnancy Outcomes In Women With Heritable Thoracic Aortic Disease: Data From The Eorp Esc Registry Of Pregnancy And Cardiac Disease (Ropac) Iii, Puck N J Peters, Johanna A Van Der Zande, Julie De Backer, Guillaume Jondeau, Osama Ahmad, Marjorie Richardson, Francesca M Comoglio, Heleen Van Der Zwaan, Siddharth K Prakash, Christina Christersson, Karishma P Ramlakhan, Roger Hall, Mark R Johnson, Jolien W Roos-Hesselink, Ropac Investigators

Faculty, Staff and Student Publications

Aims: The risk of pregnancy in women with heritable thoracic aortic disease (HTAD) is estimated to be high, but supporting data are scarce. The aim of this study is to prospectively investigate pregnancy outcomes to improve patient management and care.

Methods and results: The Registry of Pregnancy and Cardiac disease (ROPAC) III is a prospective global registry including pregnant women with known aortic pathology between 2018 and 2023. Cardiac, obstetric and fetal outcomes, beta-blocker use, and the impact of breastfeeding were investigated. Additionally, changes in aortic diameters were assessed. In total, 176 pregnancies in 170 women (mean age 32 years, …

Therapeutic Potential Of Prmt1 As A Critical Survival Dependency Target In Multiple Myeloma, Tabish Hussain, Sharad Awasthi, Farid Shahid, S Stephen Yi, Nidhi Sahni, C Marcelo Aldaz

Faculty, Staff and Student Publications

Multiple myeloma (MM) is a neoplasm of antibody-producing plasma cells and is the second most prevalent hematological malignancy worldwide. Development of drug resistance and disease relapse significantly impede the success of MM treatment, highlighting the critical need to discover novel therapeutic targets. In a custom CRISPR/Cas9 screen targeting 197 DNA damage response-related genes, Protein Arginine N-Methyltransferase 1 (PRMT1) emerged as a top hit, revealing it as a potential therapeutic vulnerability and survival dependency in MM cells. PRMT1, a major Type I PRMT enzyme, catalyzes the asymmetric transfer of methyl groups to arginine residues, influencing gene transcription and protein function through …

Genetic Contribution To Treatment-Related Dyslipidemia In Adult Survivors Of Childhood Cancer: Findings From The Ccss, Sjlife, And Dccss-Later Cohorts, Melissa Bolier, Vincent G Pluimakers, Linda Broer, Sebastian J C M M Neggers, Demi T C De Winter, Fan Wang, Jessica L Baedke, André G Uitterlinden, Kateryna Petrykey, Leontien C M Kremer, Jacqueline J Loonen, Marloes Louwerens, Heleen J Van Der Pal, E Lieke A M Feijen, Kevin C Oeffinger, Rebecca M Howell, Eric J Chow, Wendy M Leisenring, Maria Monica M Gramatges, Lindsay M Morton, Leslie L Robison, Melissa M Hudson, Kirsten K Ness, Yadav Sapkota, Gregory T Armstrong, Smita Bhatia, Yutaka Yasui, Marry M Van Den Heuvel-Eibrink

Faculty, Staff and Student Publications

Background: Dyslipidemia can occur as a long-term side effect of childhood cancer treatment. The difference in prevalence among children receiving comparable treatment suggests a role for genetic variation. We conducted the first genome-wide association study on dyslipidemia in a large childhood cancer survivor cohort, using three additional cohorts for replication.

Methods: Discovery analysis was performed in the original Childhood Cancer Survivor Study (CCSS) cohort (N = 4,332). Replication analyses were carried out in the CCSS expansion (N = 2,212), St. Jude Lifetime (N = 2,829), and Dutch Childhood Cancer Survivor Study (DCCSS-LATER) (N = 1,814) cohorts. In the CCSS cohorts, …

Preclinical Fluorescence-Guided Imaging Leveraging Surrounding Sentinel Tumor Microenvironment Identifies High-Risk Premalignant Pancreatic Lesions, Shilpa Sharma, Xiaoxia Wen, Jianbo Wang, Beibei Huang, Denise A Hernandez, Cong-Dat Pham, Zhiwen Liu, Susanne Je-Han Lin, Aiko Yamaguchi, Dimitra K Georgiou, Ryan P Coll, H Charles Manning

Faculty, Staff and Student Publications

Purpose: Because surgery is the only potential cure for pancreatic cancer, high-risk premalignant pancreatic lesions often evade detection by palpation or white-light visualization, increasing the risk of recurrence. We asked whether near-infrared fluorescence imaging of tumor-associated inflammation could identify high-risk premalignant lesions, leveraging the tumor microenvironment as a sentinel of local disease and, thus, enhance surgery outcomes.

Experimental design: Fluorescence-guided surgery was performed on genetically engineered mice [Ptf1a-Cre; LSL-KrasG12D/+; Smad4flox/flox (KSC)] at discrete stages of disease progression, histologically confirmed high-risk, premalignant lesions in postnatal mice to locally advanced pancreatic tumors in adults, using the imaging agent V-1520, a translocator protein …

Early Ctdna Dynamics Inform First-Line Therapy In Patients With Extensive-Stage Small Cell Lung Cancer, Carmela Ciardullo, Luis Tobalina, T Hedley Carr, Philip Szekeres, Silvija Kraljevic, Lauren Averett Byers, Giulia Fabbri

Faculty, Staff and Student Publications

Purpose: Small cell lung cancer (SCLC) is an aggressive malignancy with a poor prognosis despite initial treatment responses. This study evaluates ctDNA for monitoring disease and assessing the efficacy of first-line therapy in patients with extensive-stage SCLC (1L ES-SCLC).

Experimental design: In the TAZMAN trial, 31 patients with 1L ES-SCLC received standard treatment with durvalumab and etoposide plus carboplatin or cisplatin. We analyzed 228 plasma samples from 27 of 31 patients using a liquid biopsy approach to detect somatic mutations and copy-number aberrations, while also accounting for clonal hematopoiesis mutations.

Results: Baseline ctDNA analysis detected somatic alterations in 96.3% of …

An Annotated Biobank Of Triple-Negative Breast Cancer Patient-Derived Xenografts Features Treatment-Naïve And Longitudinal Samples During Neoadjuvant Chemotherapy, Amanda L Rinkenbaugh, Yuan Qi, Shirong Cai, Jiansu Shao, Faiza Baameur Hancock, Sabrina L Jeter-Jones, Xiaomei Zhang, Emily Powell, Lei Huo, Rosanna Lau, Chunxiao Fu, Rebekah Gould, Petra Den Hollander, Elizabeth E Ravenberg, Jason B White, Gaiane M Rauch, Banu Arun, Clinton Yam, Alastair M Thompson, Gloria V Echeverria, Stacy L Moulder, W Fraser Symmans, Jeffrey T Chang, Helen Piwnica-Worms

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC) that fails to respond to neoadjuvant chemotherapy (NACT) can be lethal. Developing effective strategies to eradicate chemoresistant disease requires experimental models that recapitulate the heterogeneity characteristic of TNBC. To that end, we established a biobank of 92 orthotopic patient-derived xenograft (PDX) models of TNBC from the tumors of 75 patients enrolled in the ARTEMIS clinical trial (NCT02276443), including 12 longitudinal sets generated from serial patient biopsies collected throughout NACT treatment and from metastatic disease. Models were established from both chemosensitive and chemoresistant tumors, and nearly 30% of the PDX models were capable of metastasizing …

Proteomic Perspectives On Kras-Driven Cancers And Emerging Therapeutic Approaches, Ramesh Karki, Ru Chen, Sheng Pan

Faculty, Staff and Student Publications

KRAS mutations are implicated in approximately 23% of all human malignancies, with particularly high prevalence in pancreatic ductal adenocarcinoma (PDAC) (~92%), colorectal cancer (CRC) (~49%), and non-small cell lung cancer (NSCLC) (~35%). The recent approval of the KRASG12C-specific inhibitors for NSCLC represents a pivotal advancement in KRAS-targeted therapy. Nevertheless, the emergence of intrinsic and acquired resistance to KRAS-targeted therapies poses a significant clinical obstacle to targeting KRAS, which necessitates a deeper understanding of the resistance mechanisms. Recent progress in proteomic studies has enabled comprehensive profiling of the proteomic alterations driven by KRAS mutations, offering valuable insights into the disrupted KRAS …