Life Sciences Commons^™

Fusobacterium Sphaericum Sp Nov, Isolated From A Human Colon Tumor Adheres To Colonic Epithelial Cells And Induces Il-8 Secretion, Martha A Zepeda-Rivera, Yannick Eisele, Alexander Baryiames, Hanrui Wu, Claudia Mengoni, Gianmarco Piccinno, Elsa F Mcmahon, Kaitlyn D Lacourse, Dakota S Jones, Hans Hauner, Samuel S Minot, Nicola Segata, Floyd E Dewhirst, Christopher D Johnston, Susan Bullman

Faculty, Staff and Student Publications

Cancerous tissue is a largely unexplored microbial niche that provides a unique environment for the colonization and growth of specific bacterial communities, and with it, the opportunity to identify novel bacterial species. Here, we report distinct features of a novel Fusobacterium species, F. sphaericum sp. nov. (Fs), isolated from primary colon adenocarcinoma tissue. We acquire the complete closed genome and associated methylome of this organism and phylogenetically confirm its classification into the Fusobacterium genus, with F. perfoetens as its closest neighbor. Fs is phenotypically and genetically distinct, with morphological analysis revealing its coccoid shape, that while similar to …

Addressing Controversy In Fusobacterium Nomenclature: What Exactly Does “F Nucleatum” Refer To?, Martha A Zepeda-Rivera, Floyd E Dewhirst, Susan Bullman, Christopher D Johnston

Faculty, Staff and Student Publications

The F. nucleatum group (sensu lato) is historically composed of four subspecies (F. nucleatum subsp. animalis, F. nucleatum subsp. nucleatum, F. nucleatum subsp. polymorphum, F. nucleatum subsp. vincentii). Although F. nucleatum sensu lato members are typically associated with oral disease, they have recently been shown to disseminate to the gastrointestinal tract and are associated with adverse health conditions such as inflammatory bowel disease and colorectal cancer (CRC). A growing debate over the nomenclature applied to Fusobacterium taxonomy has resulted in different names for these lineages, shifting them from their historic subspecies designations to …

Profiling The Preclinical Pharmacokinetics And Biodistribution Of A Platinum(Iv)-Based Oxaliplatin Prodrug Oxalitex And Their Significance To Antitumor Response, Guangan He, Gregory D Thiabaud, Kathryn A Shelton, Luke J Segura, Jonathan F Arambula, Jonathan L Sessler, Rick A Finch, Zahid H Siddik

Faculty, Staff and Student Publications

OxaliTEX (NOVO-111) is a novel gadolinium(III) texaphyrin-platinum(IV) complex that is under development for clinical trials. It was designed as a prodrug of oxaliplatin (1,2-diaminocyclohexane-platinum(II) oxalate) tethered to a tumor-affinic texaphyrin moiety to improve drug delivery to the tumor. However, oxaliTEX was not only more effective as an antitumor agent but also better tolerated in mice. To appreciate this higher therapeutic index and advance its preclinical development, studies were undertaken to profile its plasma pharmacokinetics, distribution to tumor and normal tissues, and pharmacodynamics of the p53/p21 molecular pathway. Nude mice, with or without a subcutaneous colorectal HCT-116 xenograft harboring a phenotypically …

Fludarabine Lymphodepletion Exposure Is Associated With Toxicities After Idecabtagene-Vicleucel In Relapsed/Refractory Multiple Myeloma: Real-World Experience From The Us Myeloma Immunotherapy Consortium, Karen Sweiss, Charlotte Wagner, Eric Anto, Tom Greene, Ryan Sun, Rebecca Gonzalez, Omar Castaneda Puglianini, Ciara Freeman, Filip Ionescu, Krina Patel, Christopher Ferreri, Mahmoud Gaballa, Leyla Shune, Joseph Mcguirk, Surbhi Sidana, Vanna Hovanky, Jack Khouri, Shahzad Raza, Faiz Anwer, Danai Dima, Hamza Hashmi, James Davis, Aimaz Afrough, Gurbakhash Kaur, Larry Anderson, Peter Forsberg, Megan Herr, Doris K Hansen, Mehmet Hakan Kocoglu, Douglas Sborov

Faculty, Staff and Student Publications

Background: Idecabtagene vicleucel (ide-cel) is a BCMA-directed CAR-T associated with high response rates in relapsed/refractory multiple myeloma (RRMM), yet responses are not durable and most patients experience toxicities. Fludarabine (Flu) is a key component of lymphodepletion but exhibits significant pharmacokinetic (PK) variability.

Objective: Given Flu exposure (AUC) predicts outcomes after CD19-directed CAR-T, we hypothesized it would predict outcomes after ide-cel. Our objective was to determine the association between fludarabine AUC and clinical outcomes after standard-of-care (SOC) ide-cel.

Study design: RRMM patients receiving ide-cel from 10 US Multiple Myeloma Immunotherapy Consortium centers were retrospectively analyzed. A population PK approach using cumulative …

Distinct Clinicogenomic Features And Immunotherapy Associations In Pulmonary Sarcomatoid Carcinoma: A Multicenter Retrospective Study, Lingzhi Hong, Alessandro Di Federico, Bolun Liu, Alissa J Cooper, Joao V Alessi, Phoebe Clark, Waree Rinsurongkawong, Chingyi Young, Hui Li, Kang Qin, Muhammad Aminu, Valentina Santo, Yasir Elamin, Boris Sepesi, Jeff Lewis, Don L Gibbons, Ara A Vaporciyan, J Jack Lee, Xiuning Le, Jia Wu, Sinchita Roy-Chowdhuri, Mark J Routbort, P Andrew Futreal, John V Heymach, Mark M Awad, Adam J Schoenfeld, Jianjun Zhang, Biagio Ricciuti, Lei Deng, Natalie I Vokes

Faculty, Staff and Student Publications

Introduction: Pulmonary sarcomatoid carcinoma (PSC) is a rare NSCLC subtype with poor prognosis. Outcomes to immune checkpoint inhibitors (ICIs) and genomic features in PSC remain underexplored compared with other NSCLC subtypes.

Methods: Patients from three institutions and the National Cancer Database (NCDB) with metastatic NSCLC treated with ICI alone or with chemotherapy were identified. Clinicogenomics and treatment outcomes were compared across PSC, lung adenocarcinoma (LUAD), and lung squamous cell carcinoma (LUSC).

Results: We analyzed 4841 patients including 165 PSC cases treated with ICI-based therapy from three institutions and 201 PSC from NCDB. In MDACC, 65 (4.3%) were PSC, 1138 (75.1%) …

Benchmarking Dna Foundation Models For Genomic And Genetic Tasks, Haonan Feng, Lang Wu, Bingxin Zhao, Chad Huff, Jianjun Zhang, Jia Wu, Lifeng Lin, Peng Wei, Chong Wu

Faculty, Staff and Student Publications

The rapid evolution of DNA foundation models promises to revolutionize genomics, yet comprehensive evaluations are lacking. Here, we present a comprehensive, unbiased benchmark of five models (DNABERT-2, Nucleotide Transformer V2, HyenaDNA, Caduceus-Ph, and GROVER) across diverse genomic and genetic tasks including sequence classification, gene expression prediction, variant effect quantification, and topologically associating domain (TAD) region recognition, using zero-shot embeddings. Our analysis reveals that mean token embedding consistently and significantly improves sequence classification performance, outperforming other pooling strategies. Model performance varies among tasks and datasets; while general purpose DNA foundation models showed competitive performance in pathogenic variant identification, they were less …

A Phase 1/2 Study Of Ds-1594 Menin Inhibitor In Relapsed/Refractory Acute Leukemias, Jayastu Senapati, Marina Konopleva, Ghayas C Issa, Elias Jabbour, Tapan Kadia, Courtney Dinardo, Gautam Borthakur, Naveen Pemmaraju, Nicholas J Short, Musa Yilmaz, Indraneel Deshmukh, Joie Alvarez, Sanam Loghavi, Guilin Tang, Hussein A Abbas, Michael Andreeff, Kapil Bhalla, Narasimha M Midde, Nabil Said, Amy Noyalis, Derek E Mires, Jing Ning, Lianchun Xiao, Farhad Ravandi, Guillermo Garcia-Manero, Hagop M Kantarjian, Naval G Daver

Faculty, Staff and Student Publications

Several menin inhibitors are in development targeting menin dependent leukemias, however available preclinical results show variable level of activity. We report the phase 1 portion (to establish a recommended phase 2 dose [RP2D]) and pharmacokinetic analysis of a phase 1/2 first-in-human clinical trial of DS-1594b menin inhibitor. Eligible patients included adults (≥ 18 years of age) with relapsed/refractory (R/R) acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) including but not restricted to those with KMT2A-rearrangement (r) or NPM1 mutation. Seventeen patients at a median of age 56 years (range, 19-82 years) were treated, 15 (88%) had R/R AML, and …

Dna Extrusion Size Determines Pathway Choice During Cag Repeat Expansion, Mayuri Bhatia, Ashutosh S. Phadte, Anna Lakhina, Anthony R. Monte Carloi Iii, Sarah Barndt, Anna Pluciennik

Department of Biochemistry and Molecular Biology Faculty Papers

DNA triplet repeat expansion causes several primarly neurological disorders like Huntington's disease, myotonic dystrophy type 1, and fragile-X related disorders. There is general consensus that recognition of extrahelical extrusions or hairpin-loop structures (formed by strand slippage) by the DNA mismatch repair protein MutSβ leads to repeat expansion by a mutagenic process. By contrast, the FAN1 nuclease attenuates triplet repeat expansion, the molecular basis of which was explained by our recent finding that FAN1 nuclease cleaves and initiates removal of extrahelical extrusions. Here we show that extrusions containing two or more triplet repeats are subject to recognition and processing by either …

Predicting The Response Of Triple Negative Breast Cancer To Neoadjuvant Systemic Therapy Via Biology-Based Modeling And Habitat Analysis, Casey E Stowers, Chengyue Wu, Clinton Yam, Jingfei Ma, Gaiane M Rauch, Thomas E Yankeelov

Faculty, Staff and Student Publications

Despite being the standard-of-care treatment, neoadjuvant therapy (NAT) attains a complete response only in approximately half of the patients with triple negative breast cancer. Thus, methods to predict and optimize patient response to NAT are needed. Previously, we employed patient-specific MRI data to calibrate a biology-based mathematical model that describes cell movement, proliferation, and death due to drug at the tumor level and cell proliferation at an image voxel level. We now extend our approach by using MRI data to group voxels into "habitats" whereby tumor cells of a habitat share the same proliferation. With this approach, we now calibrate …

Loss Of Idh1 And Idh2 Mutations During The Evolution Of Metastatic Chondrosarcoma, William Cross, Iben Lyskjær, Christopher Davies, Abigail Bunkum, Ana Maia Rocha, Tom Lesluyes, Fernanda Amary, Roberto Tirabosco, Cristina Naceur-Lombardelli, Mariam Jamal-Hanjani, Charles Swanton, Nischalan Pillay, Simone Zaccaria, Adrienne M Flanagan, Peter Van Loo

Faculty, Staff and Student Publications

Driver mutations in IDH1 and IDH2 are initiating events in the evolution of chondrosarcoma and several other cancer types. Here, we present evidence that mutant IDH1 is recurrently lost in metastatic central chondrosarcoma. This may reflect either relaxed positive selection for the mutant IDH1 locus, or negative selection for the hypermethylation phenotype later in tumor evolution. This finding highlights the challenge for therapeutic intervention by mutant IDH1 inhibitors in chondrosarcoma.

Targeting The Hepatic Circadian Clock Concomitant With Tyrosine Kinase Inhibition Reverses Late-Stage Hepatocellular Carcinoma, Baharan Fekry, Savera Aggarwal, Rachel Van Drunen, Rafael Bravo, Andy Escalante, Constance Atkins, Sheng Pan, Zheng Chen, Kai Sun, David R Hall, Mamoun Younes, Kristin Eckel-Mahan

Faculty, Staff and Student Publications

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths. Most patients present at advanced stages, and the effectiveness of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors is constrained by limited patient response. A subset of HCC shows elevated expression of the promoter 2 ("P2")-driven hepatocyte nuclear factor 4 alpha (HNF4α) isoform, which directly transcriptionally represses the circadian brain and muscle ARNT-like protein 1 (BMAL1) transcription factor. This subtype of HCC is robustly inhibited by the plant-based flavonoid nobiletin (NOB), a circadian-fortifying compound. Using patient-matched human HCC and serum, we show that BMAL1-deficient HCC shows exaggerated carnitine palmitoyl transferase …

Optimizing Lower Intensity Triplet Therapy In Acute Myeloid Leukemia: A Practical Guide, Wei-Ying Jen, Curtis A Lachowiez, Jennifer Marvin-Peek, Jessica K Altman, Musa Yilmaz, Jacqueline S Garcia, Yasmin Abaza, Nicholas J Short, Joshua F Zeidner, Naval G Daver, Andrew H Wei, Ghayas C Issa, Courtney D Dinardo

Faculty, Staff and Student Publications

Venetoclax-based doublets with azacitidine or low dose cytarabine are the standard of care for the treatment of acute myeloid leukemia (AML) in older patients or those unfit for intensive chemotherapy. However, some patients do not attain complete remission, and over time, most patients relapse. Frontline triplet therapy incorporating a targeted therapy (FLT3, IDH or menin inhibitor) is an emerging treatment concept under investigation for this population. Initial triplet regimens have yielded encouraging composite complete remission and measurable residual disease negativity rates, enabling the transition to allogeneic stem cell transplantation for eligible patients. While effective, triplets are associated with myelosuppression and …

Nivolumab Plus Ipilimumab Induce Hyper-Progression In Renal Medullary Carcinoma: Results Of A Phase Ii Trial And Preclinical Evidence, Melinda Soeung, Xinmiao Yan, Ciro Zanca, Jing Qian, Menuka Karki, Fei Duan, Hania Khan, Li Zhang, David H Peng, Mariah Williams, Rong He, Ziheng Chen, Luigi Perelli, Jianfeng Chen, Rebecca S Tidwell, Pankaj K Chauhan, Courtney N Le, Truong N A Lam, Nirjar Bhattacharya, Rutvi Shah, I-Lin Ho, Jason P Gay, Caroline C Carrillo, Ningping Feng, Kang Le, Guang Gao, Teresa L Perry, Faika Mseeh, Yongying Jiang, Quanyun A Xu, Niki Marie Zacharias, Rahul A Sheth, Tharakeswara K Bathala, Priya Rao, Najat C Daw, Durga N Tripathi, Cheryl L Walker, Mohammad M Mohammad, Jianhua Zhang, Guangchun Han, Yanshuo Chu, Ruiping Wang, Minghao Dang, Enyu Dai, Fuduan Peng, Yunhe Liu, Akshaya Jadhav, Wenhua Lang, Claudio A Arrechedera, Leticia Campos Clemente, Edwin R Parra, Hsinyi Lu, Cara L Haymaker, Ignacio I Wistuba, Andrew Futreal, Andrea Viale, Michael J Soth, Philip Jones, Joseph R Marszalek, Timothy Heffernan, Giulio F Draetta, Nizar M Tannir, Jianjun Gao, Linghua Wang, Giannicola Genovese, Pavlos Msaouel

Faculty, Staff and Students Publications

Therapeutic options for patients with renal medullary carcinoma (RMC) are limited. Here we report the results of a phase II clinical trial (NCT03274258) of anti-PD1 nivolumab plus anti-CTLA4 ipilimumab in patients with RMC, with objective response rate as primary outcome. Enrollment was halted for futility at a prespecified interim analysis as all 10 treated patients experienced rapid disease progression. 5/10 met radiological criteria for hyperprogression and median progression-free survival (secondary outcome) was 1.38 months (95% confidence interval: 1.28, 1.60). In a post-hoc single-cell RNA sequencing analysis, data from patients with RMC before and after nivolumab plus ipilimumab treatment indicated that …

Coordinated Transfer Of Dna Between Pol Θ And Pol Δ Resets Microhomology Choice During Double-Strand Break Repair, Yuzhen Li, Mark Returan, Adele T Guerin, April M Averill, Dorcas Oladapo, Sylvie Doublié, Richard D Wood

Faculty, Staff and Student Publications

DNA polymerase theta (Pol θ)-mediated end joining (TMEJ) initiates DNA double-strand break repair by using short homologies (microhomologies) between single-stranded DNA tails. This repair process is particularly important in cancer cells defective in homologous recombination. The exonuclease function of DNA polymerase delta (Pol δ) has been identified as an essential component for TMEJ, functioning to remove unpaired bases flanking a microhomology (MH). It is not known if the exonuclease removes all unpaired bases at once and how this removal might affect subsequent MH selection. Here, we reconstituted a functional TMEJ repair process using purified human Pol θ and Pol δ. …

Live-Cell Quantitative Monitoring Reveals Distinct, High-Affinity Gβγ Regulations Of Girk2 And Girk1/2 Channels, Reem Handklo-Jamal, Tal Keren Raifman, Boris Shalomov, Patrick Hofer, Uri Kahanovitch, Theres Friesacher, Galit Tabak, Vladimir Tsemakhovich, Haritha P Reddy, Orna Chomsky-Hecht, Debi Ranjan Tripathy, Kerstin Zuhlke, Carmen W Dessauer, Enno Klussmann, Yoni Haitin, Joel A Hirsch, Anna Stary-Weinzinger, Daniel Yakubovich, Nathan Dascal

Faculty, Staff and Student Publications

Gi/o protein-coupled receptors (GPCRs) inhibit cardiac and neuronal excitability via G protein-activated K+ channels (GIRK), assembled by combinations of GIRK1 - GIRK4 subunits. GIRKs are activated by direct binding of the Gβγ dimer of inhibitory Gi/o proteins. However, key aspects of this textbook signaling pathway remain debated. Recent studies suggested no Gi/o-GIRK pre-coupling and low (>250 µM) Gβγ-GIRK interaction affinity, contradicting earlier sub-µM estimates and implying low signaling efficiency. We show that Gγ prenylation, which mediates Gβγ membrane attachment required for GIRK activation, also contributes to the Gβγ-GIRK interaction, explaining the poor affinity obtained with non-prenylated Gβγ. Using quantitative …

Stiefel Md Anderson Oropharynx Cancer (Mda-Opc) Cohort: A Single-Institution, Prospective Longitudinal Outcomes Study, Amy Moreno, Ariana J Sahli, Faye Johnson, Xiaowen Sun, Carly Barbon, Waree Rinsurongkawong, Wenye Song, Flavie M Luciani, Han Liang, Jun Li, Wei Liu, J Jack Lee, S J Frank, Stephen Lai, Clifton Fuller, Katherine Hutcheson

Faculty, Staff and Student Publications

Purpose: The MD Anderson Oropharynx Cancer (MDA-OPC) cohort is a unique single-institution, prospective longitudinal cancer cohort. The cohort aims to enhance the therapeutic index of OPC management by supporting data needs for independent investigators to conduct rigorous observational studies examining exposures and factors associated with acute and late toxicities, cancer progression, recurrence, new malignancies and quality of life in OPC survivors.

Participants: A total of 1811 patients with OPC with a minimum follow-up of 6 months have been consented to our prospective registry between 18 March 2015 and 29 December 2023. Clinical and treatment (Tx) data are available on all …

Naphthalimide-Based Type-I Nano-Photosensitizers For Enhanced Antitumor Photodynamic Therapy: H2s Synergistically Regulates Pet And Self-Assembly, Huiyu Niu, Songnan Wang, Yang Liu, Nana Ma, Shuaiwei Cheng, Beidou Feng, Hyunsun Jeong, Yonggang Yang, Ge Wang, Tony D James, Juyoung Yoon, Jonathan L Sessler, Hua Zhang

Faculty, Staff and Student Publications

Photodynamic therapy (PDT) relies on a combination of light and photosensitizers (PSs) to achieve local control over cancerous lesions. However, it is subject to limitations, including tumor hypoxia, low tumor targeting, off‐target phototoxicity, and always‐on fluorescence. Here, we propose a design strategy for activated nano‐PSs (N‐PSs) to simultaneously overcome the limitations of PDT, wherein photoinduced electron transfer (PeT) is coupled with an endogenous H2S‐regulated self‐association process to promote Type‐I photochemical reactions. Using theoretical calculations, spectral analysis, and microscopic imaging, we verified the generation of self‐assembly and occurrence of PeT. And it was also shown that H2S could synergistically inhibit the …

Analysis Of A Deeply-Phenotyped Familial Hypercholesterolemia Cohort From Mexico Shows A Role For Both Rare And Common Alleles Across Known Dyslipidemia Genes And Reveals Structural Variation In A Novel Locus, Nicholas Katsanis, Niki Mourtzi, Consuelo D Quinto-Cortés, Alexandro J Martagon, Alexander G Ioannidis, Francisco M De La Vega, Jeff Gulcher, Ming Ta Michael Lee, Mohammad A Faghihi, Arturo Lopez-Pineda, Sonia Moreno-Grau, Daniel Mas Montserrat, Míriam Barrabés, David Bonet, Pavel Salazar Fernandez, Jeff Wall, Babak Moatamed, Roopa Mehta, Gabriela A Galan-Ramirez, Rafael Zubirán, Daniel Elias-Lopez, Teresa Tusié-Luna, Carlos A Aguilar-Salinas, Carlos D Bustamante

Faculty, Staff and Student Publications

Familial hypercholesterolemia (FH) is a genetic disorder driven in part by mutations in three genes that encode components of the cholesterol pathway: LDLR, APOB, and PCSK9. However, the majority of FH genetics has been performed in individuals of European descent. Here, we leveraged a cohort of 300 patients from the Mexican FH registry to understand how rare, high liability alleles and common variants might contribute to shaping individual risk. Using a combination of whole exome and of short- and long-read whole genome sequencing, we report three key findings. First, we observed that rare pathogenic point mutations and structural variants in …

Five-Year Follow-Up Analysis Of Zuma-5: Axicabtagene Ciloleucel In Relapsed/Refractory Indolent Non-Hodgkin Lymphoma, Sattva S Neelapu, Julio C Chavez, Alison R Sehgal, Narendranath Epperla, Matthew L Ulrickson, Emmanuel Bachy, Pashna N Munshi, Carla Casulo, David G Maloney, Sven De Vos, Ran Reshef, Lori A Leslie, Olalekan O Oluwole, Ibrahim Yakoub-Agha, Rashmi Khanal, Joseph D Rosenblatt, Jacob Wulff, Rhine R Shen, Wangshu Zhang, Soumya Poddar, Harry Miao, Olga Nikolajeva, Caron A Jacobson

Faculty, Staff and Student Publications

Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) follicular lymphoma (FL). Here, we report updated clinical outcomes from ZUMA-5 in 159 enrolled patients with R/R indolent non-Hodgkin lymphoma (iNHL; 127 with FL and 31 with marginal zone lymphoma) after a median follow-up of 64.6 months. Patients underwent leukapheresis and received lymphodepleting chemotherapy and axi-cel (2 × 106 CAR T cells/kg). The overall response rate was 90% (75% complete response rate). The median duration of response was 60.4 months, and the median progression-free survival (PFS) was 62.2 months; median time to next …

Tca Cycle Mode Switch Determines The Fate Of Pirtobrutinib-Tolerant Persister Cells In Mantle Cell Lymphoma, Wei Wang, Qingsong Cai, Yang Liu, Lei Nie, Heng-Huan Lee, Fangfang Yan, Yue Fei, Yixin Yao, Yijing Li, Lin Tan, Philip L Lorenzi, Ying-Nai Wang, Jun Yao, Zhihong Chen, Joseph Mitchell Mcintosh, Cheng-Tai Yu, Preetesh Jain, Vivian C Jiang, Jovanny Vargas, Xiaolin Li, Tianci Zhang, Shaoying Li, David Santos, Selvi Thirumurthi, Erin Heather Seeley, Lukas Mikolaj Simon, Christopher Flowers, Chi Young Ok, Michael Wang

Faculty, Staff and Student Publications

Bruton tyrosine kinase inhibitors (BTKis) and cell therapy have successfully been used to treat mantle cell lymphoma (MCL). However, therapy resistance inevitably emerges. Cancer cells can progressively develop stable resistance by traversing through a transient drug-tolerant persister (DTP) state. The mechanisms enabling DTP cells to reversibly adapt to therapies and evolve to acquire heterogeneity remain poorly understood, and characterizing DTP cells in MCL continues to pose a challenge for clinic translation. Here, using pirtobrutinib, a recently US Food and Drug Administration-approved noncovalent BTKi, we identified pirtobrutinib-tolerant persister cells exhibiting morphological variability by presenting a unique population of enlarged cells (giant …

Voices: Future Directions In Targeting The Tumor Microenvironment, Tanja De Gruijl, Catherine Sautès-Fridman, Daniela S Thommen, Michael A Curran

Faculty, Staff and Student Publications

What do you envision as the most promising future directions for therapeutic strategies aimed at modulating the tumor microenvironment?

Prognosis And Treatment Response Stratification According To Loss Of Proofreading (Lop), Giulia Maddalena, Fadl A Zeineddine, Saikat Chowdhury, Mohammad A Zeineddine, Abdelrahman M Yousef, Francesca Bergamo, Sara Lonardi, Timothy A Yap, Michael Geoffrey White, Michael J Overman, Scott Kopetz, John Paul Shen

Faculty, Staff and Student Publications

Background: Only a subset of polymerase epsilon (POLE) mutations is associated with hypermutant phenotype; we hypothesized that only loss-of-proofreading (LOP) POLE mutations are associated with favorable immunotherapy response.

Methods: This retrospective cohort study included a pan-cancer cohort of 69,223 patients from cBioPortal and a cohort of patients with 41 POLE mutant metastatic colorectal (CRC) treated with immunotherapy at the MD Anderson Cancer Center between January 2017 and May 2023. We evaluated prognosis according to POLE mutation functionality.

Results: In the pan-cancer cBioPortal cohort (n=69,223) POLE was mutated in 2.8% (1,965) of tumors; of these, only 7.5% (n=148) had …

Insights Into The Relevance Of Targeting Fibroblasts To Control Cancer, Viktoria Boeker, Raghu Kalluri

Faculty, Staff and Student Publications

Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) have garnered significant research attention in the last decade. As key stromal cells of the TME, studies have explored them as a potential target for controlling cancer. Using high-throughput technologies like single-cell RNA sequencing coupled with proteomics, the classification of different CAF subgroups reveals a complex system that varies by cancer type. Unraveling novel big data, potentially through AI platforms, will be key to identifying the role of CAFs in tumor progression and therapy escape mechanisms, enabling new therapies that manipulate CAFs to increase patients' survival. We summarize and discuss new developments …

Identification Of Therapeutic Targets For Renal Medullary Carcinoma Via Integrated Genomic And Transcriptomic Profiling, Pavlos Msaouel, Nizar M Tannir, Funda Meric-Bernstam, Jennifer M King, Martin H Voss, Jessica P Cheng, Susan S Thomas, Zita D Lim, Menuka Karki, Rong He, Giannicola Genovese, Rahul A Sheth, Davis R Ingram, Diana Shamsutdinova, Khalida M Wani, Wei-Lien Wang, Alexander J Lazar, Dominique Knipper-Davis, Amber Berlinski, Tayla Soares, Danil Stupichev, Kirill Kryukov, Suren Davitavyan, Anna Novokreshchenova, Dmitry Lebedev, Stanislav Kurpe, Andrey Kravets, Dmitrii Belousov, Michael Hensley, Alexander Bagaev, Francesca Paradiso, Vladimir Kushnarev

Faculty, Staff and Student Publications

Renal medullary carcinoma (RMC) is a rare but highly aggressive kidney cancer that resists conventional therapies. To identify therapeutic targets, this study employs histopathologic, genomic, and transcriptomic profiling of 25 RMC samples. TROP2, EPCAM, CLDN6, and CDH6 are significantly overexpressed compared with other renal and solid tumors. Pathway analyses indicate Hippo pathway upregulation and a tumor microenvironment rich in fibroblasts and neutrophils. We subsequently explore treatment of four heavily pretreated patients, all with high TROP2 expression, using sacituzumab govitecan, a TROP2-targeted antibody-drug conjugate. Of these four patients, one patient achieves a partial response with symptom improvement, two patients maintain stable …

Using Machine Learning For Early Prediction Of In-Hospital Mortality During Icu Admission In Liver Cancer Patients, Zhuo Zheng, Jinhong Xia, Jiawei Luo, Lei Du, Xiaobo Zhou, Xiaoyan Yang, Yan Xia, Mengyao Liu, Shixin Huang

Faculty, Staff and Student Publications

Liver cancer has a high incidence and mortality rate globally, particularly in patients requiring intensive care unit (ICU) admission. Early prediction of in-hospital mortality for these patients is crucial, yet lacking reliable tools. This study aims to develop and evaluate machine learning (ML) models for predicting in-hospital mortality in critically ill liver cancer patients admitted to the ICU. This retrospective study used data from the MIMIC-III and MIMIC-IV databases, including 862 patients from MIMIC-III (training cohort) and 692 patients from MIMIC-IV (validation cohort). The study focused on patients diagnosed with liver cancer, identified by specific ICD codes. Four ML algorithms, …

Multiomic Analysis Reveals A Key Bcat1 Role In Mtor Activation By B Cell Receptor And Tlr9, Rui Guo, Yizhe Sun, Matthew Y Lim, Hardik Shah, Joao A Paulo, Rahaman A Ahmed, Weixing Li, Yuchen Zhang, Haopeng Yang, Liang Wei Wang, Daniel Strebinger, Nicholas A Smith, Meng Li, Merrin Man Long Leong, Michael Lutchenkov, Jin Hua Liang, Zhixuan Li, Yin Wang, Rishi Puri, Ari Melnick, Michael R Green, John M Asara, Adonia E Papathanassiu, Duane R Wesemann, Steven P Gygi, Vamsi K Mootha, Benjamin E Gewurz

Faculty, Staff and Student Publications

B lymphocytes play major adaptive immune roles, producing antibodies and driving T cell responses. However, how immunometabolism networks support B cell activation and differentiation in response to distinct receptor stimuli remains incompletely understood. To gain insights, we systematically investigated acute primary human B cell transcriptional, translational, and metabolomic responses to B cell receptor (BCR), TLR9, CD40-ligand (CD40L), IL-4, or combinations thereof. T cell-independent BCR/TLR9 costimulation, which drives malignant and autoimmune B cell states, highly induced transaminase branched chain amino acid transaminase 1 (BCAT1), which localized to lysosomal membranes to support branched chain amino acid synthesis and mTORC1 activation. BCAT1 inhibition …

Autostent: A Semi-Automated Approach To Designing Customized 3d-Printed Oral Radiation Stents For Patients With Head And Neck Cancer, Anshuman Agrawal, Rance B Tino, Mohamed Zaid, Millicent Roach, Lianchun Xiao, Mark S Chambers, Anna Lee, Eugene J Koay

Faculty, Staff and Student Publications

Background: Oral stents may reduce toxicities during radiation therapy for head and neck cancer (HNC). Customized 3D-printed oral stents offer faster production and achieve comparable patient-reported outcomes to conventionally fabricated stents. However, their design process remains time-consuming, lacks standardization, and relies heavily on skilled technicians. We hypothesized that semi-automating the design process for 3D-printed, mouth-opening, tongue-depressing (MOTD) stents could standardize the design workflow and decrease design time.

Methods: Using oral stent design principles established over decades by oral oncologists, we created a customized computer program (Autostent) using MATLAB to semi-automate the design process of MOTD stents. We subsequently compared Autostent …

Oligomeric Cystatin C Supports The Immunosuppressive Activity Of Myeloid Cells Through Interaction With Inhibitory Receptors, Chengcheng Zhang, Yubo He, Xiaoye Liu, Jingjing Xie, Meng Fang, Xing Yang, Ryan Huang, Qi Lou, Bufan Li, Ankit Gupta, Cheryl Lewis, Marc I Diamond, Ningyan Zhang, Zhiqiang An, Cheng Cheng Zhang

Faculty, Staff and Student Publications

Amyloid proteins are linked to various diseases; however, their functional roles in immunity and cancer remain unclear. Here, we establish a direct link between oligomeric cystatin C-a cysteine cathepsin inhibitor and a well-characterized amyloidogenic protein-within the tumor microenvironment and the immune inhibitory receptors LILRB2 and LILRB5 on myeloid cells. We demonstrated that human LILRB2 and LILRB5, along with their murine counterpart PIRB, serve as functional receptors for cystatin C oligomers. Engagement of these inhibitory receptors by oligomeric cystatin C enhances the immunosuppressive activity of myeloid cells, leading to T-cell suppression and tumor progression. Deletion of the CST3 gene, which encodes …

First-Line Met Tyrosine Kinase Inhibitors Versus Immunotherapy ± Chemotherapy For Patients With Met Exon 14 Skipping Mutant Metastatic Nsclc, Federica Pecci, Hui Li, Alessandro Di Federico, Jia Wu, Hong Chen, Eleonora Gariazzo, Francesco Mantuano, Edoardo Garbo, Mihaela Aldea, Valentina Santo, Don Gibbons, Hai Tran, Francesco Paoloni, Guilherme Rossato De Almeida, Giulio Metro, Andrea De Giglio, Francesco Gelsomino, Xinan Wang, Marcello Tiseo, Julia Rotow, Andrea Ardizzoni, J Jack Lee, Mark M Awad, Alfredo Addeo, Lingzhi Hong, Marcelo V Negrao, Pasi A Jänne, John V Heymach, Jianjun Zhang, Biagio Ricciuti, Xiuning Le

Faculty, Staff and Student Publications

Purpose: First-line treatment options for MET exon 14 skipping-mutant metastatic non-small cell lung cancer vary because of differences in drug approvals and clinical experience. This study investigates factors influencing outcomes with first-line MET tyrosine kinase inhibitors (TKI) versus immune checkpoint inhibitors (ICI) ± chemotherapy.

Experimental design: Clinicopathologic data were collected from patients with metastatic MET exon 14 skipping-mutant non-small cell lung cancer treated with first-line MET TKI or ICI ± chemotherapy at five centers. Primary endpoints were real-world progression-free survival (rwPFS) and overall survival (OS) to first-line MET TKI versus ICI ± chemotherapy. Subgroup analyses by clinical and tumor characteristics …

Culture-Independent Meta-Pangenomics Enabled By Long-Read Metagenomics Reveals Associations With Pediatric Undernutrition, Jeremiah J Minich, Nicholas Allsing, M Omar Din, Michael J Tisza, Kenneth Maleta, Daniel Mcdonald, Nolan Hartwick, Allen Mamerto, Caitriona Brennan, Lauren Hansen, Justin Shaffer, Emily R Murray, Tiffany Duong, Rob Knight, Kevin Stephenson, Mark J Manary, Todd P Michael

Faculty, Staff and Students Publications

The human gut microbiome is linked to child malnutrition, yet traditional microbiome approaches lack resolution. We hypothesized that complete metagenome-assembled genomes (cMAGs), recovered through long-read (LR) DNA sequencing, would enable pangenome and microbial genome-wide association study (GWAS) analyses to identify microbial genetic associations with child linear growth. LR methods produced 44-64× more cMAGs per gigabase pair (Gbp) than short-read methods, with PacBio (PB) yielding the most accurate and cost-effective assemblies. In a Malawian longitudinal pediatric cohort, we generated 986 cMAGs (839 circular) from 47 samples and applied this database to an expanded set of 210 samples. Machine learning identified species …