Biomedical Informatics Commons^™

Anti-Cd137 Agonist Antibody-Independent And Clinically Feasible Preparation Of Tumor-Infiltrating Lymphocytes From Soft Tissue Sarcoma And Osteosarcoma, Yining Jin, Zhiliang Jia, Xueqing Xia, Nancy B Gordon, Joseph A Ludwig, Neeta Somaiah, Shulin Li

Faculty, Staff and Student Publications

Background: Tumor infiltrating lymphocytes (TILs) therapy has been proved for treatment of metastatic melanoma and is under investigation for other types of solid tumors. However, these successes are threatened by discontinued supply of GMP-grade anti-CD137 agonist, a key TIL preparation reagent. Therefore, exploring a GMP-adherent method for expanding endogenous TILs without anti-CD137 agonist is urgent. Toward this end, we aimed to establish an anti-CD137-independent and clinically feasible TIL expansion protocol to prepare TILs from under investigated sarcoma tumors.

Methods: We collected resected tumors from patients and cut tissues into fragments. We used IL-2 and T-cell activator CD3/CD28 without anti-CD137 agonist …

A Cytotoxic Peptide-Drug Conjugate For Tumor-Specific Delivery Of Co-Injected Molecules, Norio Miyamura, Chisato M Yamazaki, Yasuaki Anami, Kyoji Tsuchikama, Kazuki N Sugahara

Faculty, Staff and Student Publications

An ideal cancer therapy enhances anti-tumor effects while minimizing side effects. iRGD, a non-cytotoxic peptide that activates a tumor-specific molecular transport machinery, promotes the penetration of co-injected drugs into tumor tissues. Clinical trials have demonstrated its potential as a tumor-specific delivery scaffold and potentiator of anti-cancer agents. In this study, we synthesized an iRGD conjugate containing monomethyl auristatin F (MMAF), a highly toxic antimitotic agent, and characterized its dual function as a tumor-specific cytotoxic agent and co-injected drug delivery scaffold. The iRGD-MMAF conjugate internalized and killed cultured tumor cells in an αv integrin-dependent manner. When injected systemically, iRGD-MMAF homed selectively …

Efficacy Of Nampt Inhibition In T-Cell Acute Lymphoblastic Leukemia, Chelsea Vrana, Matthew Zhang, Max Rochette, Michelle Alozie, Hailey Oviedo, Alan Gonzalez, Jaden Sherman, Barry Zorman, Pavel Sumazin, Karen R Rabin, Jacob J Junco

Faculty, Staff and Students Publications

Novel agents targeting upregulated signaling pathways are needed to improve outcomes in T-cell acute lymphoblastic leukemia (T-ALL), since conventional cytotoxic chemotherapy regimens have reached the limits of tolerability. We identified upregulated, targetable signaling pathways common to both human T-ALL samples and a KrasLSL-G12D/+.Mb1Cre/+ murine model of T-ALL. We found the NAMPT inhibitor FK866 had the greatest cytotoxicity of a panel of small molecule inhibitors tested in human and mouse T-ALL cell lines, and in patient derived xenograft (PDX)-expanded T-ALL patient samples. We subsequently tested FK866 in vivo in PDX mouse models of T-ALL, and found that it significantly reduced the …

Nos Inhibition Sensitizes Metaplastic Breast Cancer To Pi3k Inhibition And Taxane Therapy Via C-Jun Repression, Tejaswini Reddy, Akshjot Puri, Liliana Guzman-Rojas, Christoforos Thomas, Wei Qian, Jianying Zhou, Hong Zhao, Bijan Mahboubi, Adrian Oo, Young-Jae Cho, Baek Kim, Jose Thaiparambil, Roberto Rosato, Karina Ortega Martinez, Maria Florencia Chervo, Camila Ayerbe, Noah Giese, David Wink, Stephen Lockett, Stephen Wong, Jeffrey Chang, Savitri Krishnamurthy, Clinton Yam, Stacy Moulder, Helen Piwnica-Worms, Funda Meric-Bernstam, Jenny Chang

Faculty, Staff and Student Publications

Metaplastic breast cancer (MpBC) is a highly chemoresistant subtype of breast cancer with no standardized therapy options. A clinical study in anthracycline-refractory MpBC patients suggested that nitric oxide synthase (NOS) inhibitor NG-monomethyl-l-arginine (L-NMMA) may augment anti-tumor efficacy of taxane. We report that NOS blockade potentiated response of human MpBC cell lines and tumors to phosphoinositide 3-kinase (PI3K) inhibitor alpelisib and taxane. Mechanistically, NOS blockade leads to a decrease in the S-nitrosylation of c-Jun NH

Parp Inhibition Radiosensitizes Brca1 Wildtype And Mutated Breast Cancer To Proton Therapy, Mariam Ben Kacem, Scott J Bright, Emma Moran, David B Flint, David K J Martinus, Broderick X Turner, Ilsa Qureshi, Rishab Kolachina, Mandira Manandhar, Poliana C Marinello, Simona F Shaitelman, Gabriel O Sawakuchi

Faculty, Staff and Student Publications

Aggressive breast cancers often fail or acquire resistance to radiotherapy. To develop new strategies to improve the outcome of aggressive breast cancer patients, we studied how PARP inhibition radiosensitizes breast cancer models to proton therapy, which is a radiotherapy modality that generates more DNA damage in the tumor than standard radiotherapy using photons. Two human BRCA1-mutated breast cancer cell lines and their isogenic BRCA1-recovered pairs were treated with a PARP inhibitor and irradiated with photons or protons. Protons (9.9 and 3.85 keV/µm) induced higher cell kill independent of BRCA1 status. PARP inhibition amplified the cell kill effect to both photons …

Inhibition Of Microrna-660-5p Decreases Breast Cancer Progression Through Direct Targeting Of Tmem41b, Valeria Villarreal-García, José Roberto Estupiñan-Jiménez, Vianey Gonzalez-Villasana, Pablo E Vivas-Mejía, Marienid Flores-Colón, Irma Estefanía Ancira-Moreno, Patricio Adrián Zapata-Morín, Claudia Altamirano-Torres, José Manuel Vázquez-Guillen, Cristina Rodríguez-Padilla, Recep Bayraktar, Mohamed H Rashed, Cristina Ivan, Gabriel Lopez-Berestein, Diana Reséndez-Pérez

Faculty, Staff and Student Publications

Background: Breast cancer is the most prevalent cancer among women worldwide. Most breast cancer-related deaths result from metastasis and drug resistance. Novel therapies are imperative for targeting metastatic and drug-resistant breast cancer cells. Accumulating evidence suggests that dysregulated microRNAs (miRNAs) promote breast cancer progression, metastasis, and drug resistance. Compared with healthy breast tissue, miR-660-5p is notably overexpressed in breast cancer tumor tissues. However, the downstream effectors of miR-660-5p in breast cancer cells have not been fully elucidated. Our aim was to investigate the role of miR-660-5p in breast cancer cell proliferation, migration, invasion, and angiogenesis and to identify its potential …

Enhancer Reprogramming Underlies Therapeutic Utility Of A Smarca2 Degrader In Smarca4 Mutant Cancer, Sasikumar Kotagiri, Nicholas Blazanin, Yuanxin Xi, Yanyan Han, Md Qudratullah, Xiaobing Liang, Yawen Wang, Poonam Pandey, Hira Mazhar, Truong Nguyen Lam, Anand Kamal Singh, Jing Wang, Yonathan Lissanu

Faculty, Staff and Student Publications

Genomic studies have identified frequent mutations in subunits of the SWI/SNF (switch/sucrose non-fermenting) chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer (NSCLC). Genetic evidence indicates that the paralog SMARCA2 is synthetic lethal to SMARCA4 suggesting SMARCA2 is a valuable therapeutic target. However, the discovery of selective inhibitors of SMARCA2 has been challenging. Here, we utilized structure-activity relationship (SAR) studies to develop YD23, a potent and selective proteolysis targeting chimera (PROTAC) targeting SMARCA2. Mechanistically, we show that SMARCA2 degradation induces reprogramming of the enhancer landscape in SMARCA4-mutant cells with loss of chromatin accessibility at enhancers of genes …

Co-Inhibition Of Tgli1 And Gp130 Using Fda-Approved Ketoconazole And Bazedoxifene Is Synergistic Against The Growth And Metastasis Of Her2-Enriched And Triple-Negative Breast Cancers, Sara Manore, Chuling Zhuang, Mariana K Najjar, Grace L Wong, Shivani Bindal, Kounosuke Watabe, Jiayuh Lin, Hui-Wen Lo

Faculty, Staff and Student Publications

Breast cancer stem cells (CSCs) are resistant to most cancer therapeutics and contribute to tumor recurrence and metastasis. Two breast CSC-promoting transcription factors, truncated glioma-associated oncogene homolog 1 (tGLI1) and signal transducer and activator of transcription 3 (STAT3), have been reported to be frequently co-expressed in HER2-enriched breast cancer and triple-negative breast cancer (TNBC), undergo protein-protein interactions for gene regulation and activation, and functionally cooperate to promote breast CSCs. STAT3 can be activated by activated interleukin-6 receptor/glycoprotein-130 (IL-6R/GP130). Co-targeting of tGLI1 and IL-6R/GP130 has not been investigated in breast cancer or any tumor type. Here, we report that tGLI1 and …

Additional Expression Of T-Cell Engager In Clinically Tested Oncolytic Adeno-Immunotherapy Redirects Tumor-Infiltrated, Irrelevant T Cells Against Cancer Cells To Enhance Antitumor Immunity, Daisuke Morita, Amanda Rosewell Shaw, Greyson Biegert, Caroline Porter, Mae Woods, Spyridoula Vasileiou, Bora Lim, Masataka Suzuki

Faculty, Staff and Student Publications

Background: Oncolytic adenoviruses (OAds) are the most clinically tested viral vectors for solid tumors. However, most clinically tested "Armed" OAds show limited antitumor effects in patients with various solid tumors even with increased dosages and multiple injections. We developed a binary oncolytic/helper-dependent adenovirus system (CAdVEC), in which tumors are coinfected with an OAd and a non-replicating helper-dependent Ad (HDAd). We recently demonstrated that a single low-dose CAdVEC expressing interleukin-12, programmed death-ligand 1 blocker, and HSV thymidine kinase safety switch (CAdTrio) induces significant antitumor effects in patients, including complete response. Similar to previous OAd studies, all patients primarily amplified Ad-specific T …

Myeloid Activation Clears Ascites And Reveals Il27-Dependent Regression Of Metastatic Ovarian Cancer, Brennah Murphy, Taito Miyamoto, Bryan S Manning, Gauri Mirji, Alessio Ugolini, Toshitha Kannan, Kohei Hamada, Yanfang P Zhu, Daniel T Claiborne, Lu Huang, Rugang Zhang, Yulia Nefedova, Andrew Kossenkov, Filippo Veglia, Rahul Shinde, Nan Zhang

Faculty, Staff and Student Publications

Patients with metastatic ovarian cancer (OvCa) have a 5-year survival rate of < 30% due to the persisting dissemination of chemoresistant cells in the peritoneal fluid and the immunosuppressive microenvironment in the peritoneal cavity. Here, we report that intraperitoneal administration of β-glucan and IFNγ (BI) induced robust tumor regression in clinically relevant models of metastatic OvCa. BI induced tumor regression by controlling fluid tumor burden and activating localized antitumor immunity. β-glucan alone cleared ascites and eliminated fluid tumor cells by inducing intraperitoneal clotting in the fluid and Dectin-1-Syk-dependent NETosis in the omentum. In omentum tumors, BI expanded a novel subset of immunostimulatory IL27+ macrophages and neutralizing IL27 impaired BI efficacy in vivo. Moreover, BI directly induced IL27 secretion in macrophages where single agent treatment did not. Finally, BI extended mouse survival in a chemoresistant model and significantly improved chemotherapy response in a chemo-sensitive model. In summary, we propose a new therapeutic strategy for the treatment of metastatic OvCa.

Imipridones Inhibit Tumor Growth And Improve Survival In An Orthotopic Liver Metastasis Mouse Model Of Human Uveal Melanoma, Chandrani Chattopadhyay, Janos Roszik, Rajat Bhattacharya, Md Alauddin, Iqbal Mahmud, Sirisha Yadugiri, Mir Mustafa Ali, Fatima S Khan, Varun Vijay Prabhu, Philip L Lorenzi, Bo Wei, Elizabeth Burton, Rohini R Morey, Rossana Lazcano, Michael A Davies, Sapna P Patel, Elizabeth A Grimm

Faculty, Staff and Student Publications

Background: Uveal melanoma (UM) is a highly aggressive disease with very few treatment options. We previously demonstrated that mUM is characterized by high oxidative phosphorylation (OXPHOS). Here we tested the anti-tumor, signaling and metabolic effects of imipridones, which are CLPP activators, which inhibit OXPHOS indirectly and have demonstrated safety in patients.

Methods: We assessed CLPP expression in UM patient samples. We tested the effects of imipridones (ONC201 and ONC212) on the growth, survival, signaling and metabolism of UM cell lines in vitro, and for therapeutic efficacy in vivo in UM liver metastasis models.

Results: CLPP expression was detected in primary …

Tumor Expression Of Cd83 Reduces Glioma Progression And Is Associated With Reduced Immunosuppression, Malcolm F Mcdonald, Rachel Naomi Curry, Isabella O'Reilly, Brittney Lozzi, Alexis Cervantes, Zhung-Fu Lee, Anna Rosenbaum, Peihao He, Carrie Mohila, Arif O Harmanci, Akdes Serin Harmanci, Benjamin Deneen, Ganesh Rao

Faculty, Staff and Student Publications

Immunosuppression in malignant glioma remains a barrier to therapeutic development. CD83 overexpression in human and mouse glioma increases survival. CD83+ tumor cells promote signatures related to cytotoxic T cells, enhanced activation of CD8+ T cells, and increased proinflammatory cytokines. These findings suggest that tumor-expressed CD83 could mediate tumor-immune communications.

Comparing Neoantigen Cancer Vaccines And Immune Checkpoint Therapy Unveils An Effective Vaccine And Anti-Trem2 Macrophage-Targeting Dual Therapy, Sunita Keshari, Alexander S Shavkunov, Qi Miao, Akata Saha, Tomoyuki Minowa, Martina Molgora, Charmelle D Williams, Mehdi Chaib, Anna M Highsmith, Josué E Pineda, Sayan Alekseev, Elise Alspach, Kenneth H Hu, Marco Colonna, Kristen E Pauken, Ken Chen, Matthew M Gubin

Faculty, Staff and Student Publications

The goal of therapeutic cancer vaccines and immune checkpoint therapy (ICT) is to promote T cells with anti-tumor capabilities. Here, we compared mutant neoantigen (neoAg) peptide-based vaccines with ICT in preclinical models. NeoAg vaccines induce the most robust expansion of proliferating and stem-like PD-1+TCF-1+ neoAg-specific CD8 T cells in tumors. Anti-CTLA-4 and/or anti-PD-1 ICT promotes intratumoral TCF-1- neoAg-specific CD8 T cells, although their phenotype depends in part on the specific ICT used. Anti-CTLA-4 also prompts substantial changes to CD4 T cells, including induction of ICOS+Bhlhe40+ T helper 1 (Th1)-like cells. Although neoAg vaccines or ICTs expand iNOS+ macrophages, neoAg vaccines …

A Proteogenomic Analysis Of Cervical Cancer Reveals Therapeutic And Biological Insights, Jing Yu, Xiuqi Gui, Yunhao Zou, Qian Liu, Zhicheng Yang, Jusheng An, Xuan Guo, Kaihua Wang, Jiaming Guo, Manni Huang, Shuhan Zhou, Jing Zuo, Yimin Chen, Lu Deng, Guangwen Yuan, Ning Li, Yan Song, Jia Jia, Jia Zeng, Yuxi Zhao, Xianming Liu, Xiaoxian Du, Yansheng Liu, Pei Wang, Bing Zhang, Li Ding, Ana I Robles, Henry Rodriguez, Hu Zhou, Zhen Shao, Lingying Wu, Daming Gao

Faculty, Staff and Students Publications

Although the incidence of cervical cancer (CC) has been reduced in high-income countries due to human papillomavirus (HPV) vaccination and screening strategies, it remains a significant public health issue that poses a threat to women's health in low-income countries. Here, we perform a comprehensive proteogenomic profiling of CC tumors obtained from 139 Chinese women. Integrated proteogenomic analysis links genetic aberrations to downstream pathogenesis-related pathways and reveals the landscape of HPV-associated multi-omic changes. EP300 is found to enhance the acetylation of FOSL2-K222, consequently accelerating the malignant proliferation of CC cells. Proteomic stratification identifies three patient subgroups with distinct features in prognosis, …

Epigenome Reprogramming Through H3k27 And H3k4 Trimethylation As A Resistance Mechanism To Dna Methylation Inhibition In Brafv600e-Mutated Colorectal Cancer, Hey Min Lee, Ajay Kumar Saw, Van K Morris, Stefania Napolitano, Christopher Bristow, Sanjana Srinivasan, Micheal Peoples, Alexey Sorokin, Preeti Kanikarla Marie, Jonathan Schulz, Anand K Singh, Christopher Terranova, Oluwadara Coker, Abhinav Jain, Scott Kopetz, Kunal Rai

Faculty, Staff and Student Publications

Purpose: BRAFV600E-mutated colorectal cancer exhibits a strong correlation with DNA hypermethylation, suggesting that this subgroup of tumors presents unique epigenomic phenotypes. Nonetheless, 5-azacitidine, which inhibits DNA methyltransferase activity, is not efficacious in BRAFV600E colorectal cancer in vivo.

Experimental design: We randomized and treated mice implanted with patient-derived tumor xenografts harboring BRAFV600E mutation with control, 5-azacitidine, vemurafenib (BRAF inhibitor), or the combination. Comprehensive epigenomic profiling was conducted on control and 5-azacitidine-treated tumor samples, including DNA methylation, histone modifications, chromatin accessibility, and gene expression. Combinations of epigenetic agents were explored in preclinical BRAFV600E colorectal cancer models.

Results: A profound reduction of DNA …

Low-Molecular Weight Cyclin E Confers A Vulnerability To Pkmyt1 Inhibition In Triple-Negative Breast Cancer, Mi Li, Amriti R Lulla, Yan Wang, Spyros Tsavaschidis, Fuchenchu Wang, Cansu Karakas, Tuyen D T Nguyen, Tuyen N Bui, Marc A Pina, Mei-Kuang Chen, Sofia Mastoraki, Asha S Multani, Natalie W Fowlkes, Aysegul Sahin, C Gary Marshall, Kelly K Hunt, Khandan Keyomarsi

Faculty, Staff and Student Publications

Cyclin E is a regulatory subunit of CDK2 that mediates S phase entry and progression. The cleavage of full-length cyclin E (FL-cycE) to low-molecular weight isoforms (LMW-E) dramatically alters substrate specificity, promoting G1-S cell cycle transition and accelerating mitotic exit. Approximately 70% of triple-negative breast cancers (TNBC) express LMW-E, which correlates with poor prognosis. PKMYT1 also plays an important role in mitosis by inhibiting CDK1 to block premature mitotic entry, suggesting it could be a therapeutic target in TNBC expressing LMW-E. In this study, analysis of tumor samples of patients with TNBC revealed that coexpression of LMW-E and PKMYT1-catalyzed CDK1 …

Impa1-Derived Inositol Maintains Stemness In Castration-Resistant Prostate Cancer Via Impdh2 Activation, Che-Chia Hsu, Guihua Wang, Chien-Feng Li, Xian Zhang, Zhen Cai, Tingjin Chen, Bo-Syong Pan, Rajesh Kumar Manne, Gagan Deep, Haiwei Gu, Yuzhuo Wang, Danni Peng, Vasudevarao Penugurti, Xiaobo Zhou, Zhigang Xu, Zhongzhu Chen, Ming Chen, Andrew J Armstrong, Jiaoti Huang, Hong-Yu Li, Hui-Kuan Lin

Faculty, Staff and Student Publications

Acquisition of prostate cancer stem cells (PCSCs) manifested during androgen ablation therapy (ABT) contributes to castration-resistant prostate cancer (CRPC). However, little is known about the specific metabolites critically orchestrating this process. Here, we show that IMPA1-derived inositol enriched in PCSCs is a key metabolite crucially maintaining PCSCs for CRPC progression and ABT resistance. Notably, conditional Impa1 knockout in the prostate abrogates the pool and properties of PCSCs to orchestrate CRPC progression and prolong the survival of TRAMP mice. IMPA1-derived inositol serves as a cofactor that directly binds to and activates IMPDH2, which synthesizes guanylate nucleotides for maintaining PCSCs with ARlow/- …

Microrna-1307-3p Contributes To Breast Cancer Progression Through Prm2, José Roberto Estupiñan-Jiménez, Valeria Villarreal-García, Vianey Gonzalez-Villasana, Pablo E Vivas-Mejia, Jose Manuel Vazquez-Guillen, Patricio Adrián Zapata-Morin, Marienid Flores-Colón, Claudia Altamirano-Torres, Ezequiel Viveros-Valdez, Cristina Ivan, Mohammed H Rashed, Recep Bayraktar, Cristina Rodríguez-Padilla, Gabriel Lopez-Berestein, Diana Resendez-Perez

Faculty, Staff and Student Publications

Background: Despite advances in screening and therapy, breast cancer (BC) remains the predominant cancer in women globally. Dysregulation of microRNAs (miRNAs) is pivotal in carcinogenesis across various cancers, including BC. Evidence indicates that miR-1307-3p is upregulated in BC tumors, yet its target genes are not fully elucidated. This study aimed to explore how miR-1307-3p regulates BC proliferation, migration, invasion, and angiogenesis and to identify potential target genes.

Methods: Basal miR-1307-3p levels were quantified in BC cell lines MDA-MB-231 and MCF-7, as well as MCF-10A using quantitative real-time reverse transcription-PCR (RT-qPCR). The impact of miR-1307-3p inhibition on BC cell proliferation, migration, …

Hu8f4-Car T Cells With Mutated Fc Spacer Segment Improve Target Specificity And Mediate Anti-Leukemia Activity In Vivo, Hong He, Rolando A Vedia, Sijie Lu, Qiaochuan Li, Kathryn R Cox, Lisa St John, Anna Sergeeva, Karen Clise-Dwyer, Gheath Alatrash, Elizabeth J Shpall, Qing Ma, Jeffrey J Molldrem

Faculty, Staff and Student Publications

Background aims: Hu8F4 is a T-cell receptor-like antibody with high affinity for the leukemia-associated antigen PR1/HLA-A2 epitope. Adapted into a chimeric antigen receptor (CAR) format, Hu8F4-CAR is composed of the Hu8F4 single-chain variable fragment, the human IgG1 CH2CH3 extracellular spacer domain, a human CD28 costimulatory domain and the human CD3ζ signaling domain. We have demonstrated high efficacy of Hu8F4-CAR-T cells against PR1/HLA-A2-expressing cell lines and leukemic blasts from patients with acute myeloid leukemia in vitro. Previous studies have shown that modification of the Fc domains of IgG4 CH2CH3 spacer regions can eliminate activation-induced cell death and off-target killing mediated by …

Mechanisms Of Response And Tolerance To Active Ras Inhibition In Kras-Mutant Non-Small Cell Lung Cancer, Haniel A Araujo, Ximo Pechuan-Jorge, Teng Zhou, Minh Truong Do, Xin Hu, Frank R Rojas Alvarez, Maria E Salvatierra, Heladio P Ibarguen, Richard Lee, Rashi Raghulan, Harshit Shah, Mariela A Moreno Ayala, Kevin Chen, Nataliya Tovbis Shifrin, Shuhong Wu, Luisa M Solis Soto, Marcelo V Negrao, Don L Gibbons, David S Hong, Jack A Roth, John V Heymach, Jianjun Zhang, Jingjing Jiang, Mallika Singh, Jacqueline A M Smith, Elsa Quintana, Ferdinandos Skoulidis

Faculty, Staff and Student Publications

Resistance to inactive state-selective RASG12C inhibitors frequently entails accumulation of RASGTP, rendering effective inhibition of active RAS potentially desirable. Here, we evaluated the antitumor activity of the RAS(ON) multiselective tricomplex inhibitor RMC-7977 and dissected mechanisms of response and tolerance in KRASG12C-mutant non-small cell lung cancer (NSCLC). Broad-spectrum reversible RASGTP inhibition with or without concurrent covalent targeting of active RASG12C yielded superior and differentiated antitumor activity across diverse comutational KRASG12C-mutant NSCLC mouse models of primary or acquired RASG12C(ON) or RASG12C(OFF) inhibitor resistance. Interrogation of time-resolved single-cell transcriptional responses established an in vivo atlas of multimodal acute and chronic RAS pathway inhibition …

Fractionated Photoimmunotherapy Stimulates An Anti-Tumour Immune Response: An Integrated Mathematical And In Vitro Study, Mohammad U Zahid, Matthew Waguespack, Rebecca C Harman, Eric M Kercher, Shubhankar Nath, Tayyaba Hasan, Imran Rizvi, Bryan Q Spring, Heiko Enderling

Faculty, Staff and Student Publications

Background: Advanced epithelial ovarian cancer (EOC) has high recurrence rates due to disseminated initial disease presentation. Cytotoxic phototherapies, such as photodynamic therapy (PDT) and photoimmunotherapy (PIT, cell-targeted PDT), have the potential to treat disseminated malignancies due to safe intraperitoneal delivery.

Methods: We use in vitro measurements of EOC tumour cell and T cell responses to chemotherapy, PDT, and epidermal growth factor receptor targeted PIT as inputs to a mathematical model of non-linear tumour and immune effector cell interaction. The model outputs were used to calculate how photoimmunotherapy could be utilised for tumour control.

Results: In vitro measurements of PIT dose …

Mechanisms Of Resistance To Oncogenic Kras Inhibition In Pancreatic Cancer, Julien Dilly, Megan T Hoffman, Laleh Abbassi, Ziyue Li, Francesca Paradiso, Brendan D Parent, Connor J Hennessey, Alexander C Jordan, Micaela Morgado, Shatavisha Dasgupta, Giselle A Uribe, Annan Yang, Kevin S Kapner, Felix P Hambitzer, Li Qiang, Hanrong Feng, Jacob Geisberg, Junning Wang, Kyle E Evans, Hengyu Lyu, Aislyn Schalck, Ningping Feng, Anastasia M Lopez, Christopher A Bristow, Michael P Kim, Kimal I Rajapakshe, Vahid Bahrambeigi, Jennifer A Roth, Kavita Garg, Paola A Guerrero, Ben Z Stanger, Simona Cristea, Scott W Lowe, Timour Baslan, Eliezer M Van Allen, Joseph D Mancias, Emily Chan, Abraham Anderson, Yuliya V Katlinskaya, Alex K Shalek, David S Hong, Shubham Pant, Jill Hallin, Kenna Anderes, Peter Olson, Timothy P Heffernan, Seema Chugh, James G Christensen, Anirban Maitra, Brian M Wolpin, Srivatsan Raghavan, Jonathan A Nowak, Peter S Winter, Stephanie K Dougan, Andrew J Aguirre

Faculty, Staff and Student Publications

KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+; Trp53LSL-R172H/+; p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, Cdk6, and Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. …

Car-Redirected Natural Killer T Cells Demonstrate Superior Antitumor Activity To Car-T Cells Through Multimodal Cd1d-Dependent Mechanisms, Xin Zhou, Ying Wang, Zhangqi Dou, Gloria Delfanti, Ourania Tsahouridis, Caroline Marnata Pellegry, Manuela Zingarelli, Gatphan Atassi, Mark G Woodcock, Giulia Casorati, Paolo Dellabona, William Y Kim, Linjie Guo, Barbara Savoldo, Ageliki Tsagaratou, J Justin Milner, Leonid S Metelitsa, Gianpietro Dotti

Faculty, Staff and Students Publications

Human natural killer T (NKT) cells have been proposed as a promising cell platform for chimeric antigen receptor (CAR) therapy in solid tumors. Here we generated murine CAR-NKT cells and compared them with CAR-T cells in immune-competent mice. Both CAR-NKT cells and CAR-T cells showed similar antitumor effects in vitro, but CAR-NKT cells showed superior antitumor activity in vivo via CD1d-dependent immune responses in the tumor microenvironment. Specifically, we show that CAR-NKT cells eliminate CD1d-expressing M2-like macrophages. In addition, CAR-NKT cells promote epitope spreading and activation of endogenous T cell responses against tumor-associated neoantigens. Finally, we observed that CAR-NKT cells …

Type I Met Inhibitors Cooperate With Pd-1 Blockade To Promote Rejection Of Hepatocellular Carcinoma, Ricardo Deazevedo, Madeline Steiner, Broderick X Turner, Arthur Liu, Sherwin Newton, Joanna Schmidt, Rachel Fleming, Angelica Tolentino, Ahmed O Kaseb, Michael A Curran

Faculty, Staff and Student Publications

Blockade of the immune checkpoints programmed death-1 (PD-1) and cytotoxic lymphocyte antigen 4 has improved outcomes for patients with hepatocellular carcinoma (HCC), yet most still fail to achieve objective clinical benefit. MET plays key roles in both HCC tumorigenesis and immunosuppressive conditioning; however, inhibition of MET causes upregulation of PD-ligand 1 (PD-L1) suggesting the use of these inhibitors in the context of PD-1 blockade. We sought to investigate across the Hepa1-6, HCA-1 and diethylnitrosamine (DEN) models of HCC whether the combination of more specific type I versus more pleiotropic type II MET inhibitors would confer superior outcomes in combination with …

Tumour-Intrinsic Pdl1 Signals Regulate The Chk2 Dna Damage Response In Cancer Cells And Mediate Resistance To Chk1 Inhibitors, Clare E Murray, Anand V R Kornepati, Carlos Ontiveros, Yiji Liao, Bárbara De La Peña Avalos, Cody M Rogers, Zexuan Liu, Yilun Deng, Haiyan Bai, Suresh Kari, Alvaro S Padron, Jacob T Boyd, Ryan Reyes, Curtis A Clark, Robert S Svatek, Rong Li, Yanfen Hu, Meiling Wang, José R Conejo-Garcia, Lauren A Byers, Kavya Ramkumar, Anil K Sood, Jung-Min Lee, Christin E Burd, Ratna K Vadlamudi, Harshita B Gupta, Weixing Zhao, Eloïse Dray, Patrick Sung, Tyler J Curiel

Faculty, Staff and Student Publications

Background: Aside from the canonical role of PDL1 as a tumour surface-expressed immune checkpoint molecule, tumour-intrinsic PDL1 signals regulate non-canonical immunopathological pathways mediating treatment resistance whose significance, mechanisms, and therapeutic targeting remain incompletely understood. Recent reports implicate tumour-intrinsic PDL1 signals in the DNA damage response (DDR), including promoting homologous recombination DNA damage repair and mRNA stability of DDR proteins, but many mechanistic details remain undefined.

Methods: We genetically depleted PDL1 from transplantable mouse and human cancer cell lines to understand consequences of tumour-intrinsic PDL1 signals in the DNA damage response. We complemented this work with studies of primary human tumours …

Interpreting The Biological Effects Of Protons As A Function Of Physical Quantity: Linear Energy Transfer Or Microdosimetric Lineal Energy Spectrum?, Fada Guan, Lawrence Bronk, Matthew Kerr, Yuting Li, Leslie A Braby, Mary Sobieski, Xiaochun Wang, Xiaodong Zhang, Clifford Stephan, David R Grosshans, Radhe Mohan

Faculty, Staff and Student Publications

The choice of appropriate physical quantities to characterize the biological effects of ionizing radiation has evolved over time coupled with advances in scientific understanding. The basic hypothesis in radiation dosimetry is that the energy deposited by ionizing radiation initiates all the consequences of exposure in a biological sample (e.g., DNA damage, reproductive cell death). Physical quantities defined to characterize energy deposition have included dose, a measure of the mean energy imparted per unit mass of the target, and linear energy transfer (LET), a measure of the mean energy deposition per unit distance that charged particles traverse in a medium. The …

Interpreting The Biological Effects Of Protons As A Function Of Physical Quantity: Linear Energy Transfer Or Microdosimetric Lineal Energy Spectrum?, Fada Guan, Lawrence Bronk, Matthew Kerr, Yuting Li, Leslie A Braby, Mary Sobieski, Xiaochun Wang, Xiaodong Zhang, Clifford Stephan, David R Grosshans, Radhe Mohan

Faculty, Staff and Student Publications

The choice of appropriate physical quantities to characterize the biological effects of ionizing radiation has evolved over time coupled with advances in scientific understanding. The basic hypothesis in radiation dosimetry is that the energy deposited by ionizing radiation initiates all the consequences of exposure in a biological sample (e.g., DNA damage, reproductive cell death). Physical quantities defined to characterize energy deposition have included dose, a measure of the mean energy imparted per unit mass of the target, and linear energy transfer (LET), a measure of the mean energy deposition per unit distance that charged particles traverse in a medium. The …

Interpreting The Biological Effects Of Protons As A Function Of Physical Quantity: Linear Energy Transfer Or Microdosimetric Lineal Energy Spectrum?, Fada Guan, Lawrence Bronk, Matthew Kerr, Yuting Li, Leslie A Braby, Mary Sobieski, Xiaochun Wang, Xiaodong Zhang, Clifford Stephan, David R Grosshans, Radhe Mohan

Faculty, Staff and Student Publications

The choice of appropriate physical quantities to characterize the biological effects of ionizing radiation has evolved over time coupled with advances in scientific understanding. The basic hypothesis in radiation dosimetry is that the energy deposited by ionizing radiation initiates all the consequences of exposure in a biological sample (e.g., DNA damage, reproductive cell death). Physical quantities defined to characterize energy deposition have included dose, a measure of the mean energy imparted per unit mass of the target, and linear energy transfer (LET), a measure of the mean energy deposition per unit distance that charged particles traverse in a medium. The …

Interpreting The Biological Effects Of Protons As A Function Of Physical Quantity: Linear Energy Transfer Or Microdosimetric Lineal Energy Spectrum?, Fada Guan, Lawrence Bronk, Matthew Kerr, Yuting Li, Leslie A Braby, Mary Sobieski, Xiaochun Wang, Xiaodong Zhang, Clifford Stephan, David R Grosshans, Radhe Mohan

Faculty, Staff and Student Publications

The choice of appropriate physical quantities to characterize the biological effects of ionizing radiation has evolved over time coupled with advances in scientific understanding. The basic hypothesis in radiation dosimetry is that the energy deposited by ionizing radiation initiates all the consequences of exposure in a biological sample (e.g., DNA damage, reproductive cell death). Physical quantities defined to characterize energy deposition have included dose, a measure of the mean energy imparted per unit mass of the target, and linear energy transfer (LET), a measure of the mean energy deposition per unit distance that charged particles traverse in a medium. The …

Interpreting The Biological Effects Of Protons As A Function Of Physical Quantity: Linear Energy Transfer Or Microdosimetric Lineal Energy Spectrum?, Fada Guan, Lawrence Bronk, Matthew Kerr, Yuting Li, Leslie A Braby, Mary Sobieski, Xiaochun Wang, Xiaodong Zhang, Clifford Stephan, David R Grosshans, Radhe Mohan

Faculty, Staff and Student Publications

The choice of appropriate physical quantities to characterize the biological effects of ionizing radiation has evolved over time coupled with advances in scientific understanding. The basic hypothesis in radiation dosimetry is that the energy deposited by ionizing radiation initiates all the consequences of exposure in a biological sample (e.g., DNA damage, reproductive cell death). Physical quantities defined to characterize energy deposition have included dose, a measure of the mean energy imparted per unit mass of the target, and linear energy transfer (LET), a measure of the mean energy deposition per unit distance that charged particles traverse in a medium. The …