Genetic Phenomena Commons^™

Venetoclax Consolidation In High-Risk Cll Treated With Ibrutinib For ≥1 Year Achieves A High Rate Of Undetectable Mrd, Philip A Thompson, Michael J Keating, Alessandra Ferrajoli, Nitin Jain, Christine B Peterson, Naveen Garg, Sa A Wang, Jeffrey L Jorgensen, Tapan M Kadia, Prithviraj Bose, Naveen Pemmaraju, Nicholas J Short, William G Wierda

Faculty, Staff and Student Publications

Patients receiving ibrutinib for CLL rarely achieve undetectable measurable residual disease (U-MRD), necessitating indefinite therapy, with cumulative risks of treatment discontinuation due to progression or adverse events. This study added venetoclax to ibrutinib for up to 2 years, in patients who had received ibrutinib for ≥12 months (mo) and had ≥1 high risk feature (TP53 mutation and/or deletion, ATM deletion, complex karyotype or persistently elevated β2-microglobulin). The primary endpoint was U-MRD with 10−4 sensitivity (U-MRD4) in bone marrow (BM) at 12mo. Forty-five patients were treated. On intention-to-treat analysis, 23/42 (55%) patients improved their response to CR (2 pts were …

Eliminating Breast Surgery For Invasive Cancer With Exceptional Response To Neoadjuvant Systemic Therapy: Prospective Multicenter Clinical Trial Planned Initial Feasibility Endpoint, Helen M Johnson, Vicente Valero, Wei T Yang, Benjamin D Smith, Savitri Krishnamurthy, Yu Shen, Heather Lin, Anthony Lucci, Gaiane M Rauch, Henry M Kuerer

Faculty, Staff and Student Publications

Background: Response to neoadjuvant systemic therapy (NST) for breast cancer enables tailoring of subsequent therapy. Image-guided breast biopsy after NST can accurately predict a pathologic complete response (pCR). The feasibility phase of the clinical trial reported here assesses omission of breast surgery followed by radiotherapy in terms of local recurrence before trial expansion.

Study design: Women with unicentric, cT1-2 N0-1 M0 triple-negative (TNBC) or human epidermal growth factor receptor 2-positive breast cancer (HER2+BC) cancer with < 2 cm residual disease on post-NST imaging were eligible to enroll. If no residual invasive or in situ disease was identified by image-guided, vacuum-assisted core biopsy (VACB), breast surgery was omitted, and radiotherapy delivered. The primary endpoint for the feasibility phase was ipsilateral breast tumor recurrence at 6 months. If any recurrence occurred during the feasibility phase the trial would halt.

Results: Thirteen patients were enrolled from March 2017 to October 2018. The mean age was 60.8 years (range 51 to 75) and most patients were …

Carboplatin Dosing In The Treatment Of Ovarian Cancer: An Nrg Oncology Group Study, Aaron M Praiss, Austin Miller, Judith Smith, Stuart M Lichtman, Michael Bookman, Carol Aghajanian, Paul Sabbatini, Floor Backes, David E Cohn, Peter Argenta, Michael Friedlander, Michael J Goodheart, David G Mutch, David M Gershenson, Krishnansu S Tewari, Robert M Wenham, Andrea E Wahner Hendrickson, Roger B Lee, Heidi Gray, Angeles Alvarez Secord, Linda Van Le, Roisin E O'Cearbhaill

Faculty, Staff and Student Publications

Objective: To determine the effects of using National Comprehensive Cancer Network (NCCN) guidelines to estimate renal function on carboplatin dosing and explore adverse effects associated with a more accurate estimation of lower creatinine clearance (CrCl).

Methods: Retrospective data were obtained for 3830 of 4312 patients treated on GOG182 (NCT00011986)-a phase III trial of platinum-based chemotherapy for advanced-stage ovarian cancer. Carboplatin dose per patient on GOG182 was determined using the Jelliffe formula. We recalculated CrCl to determine dosing using Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault (with/without NCCN recommended modifications) formulas. Associations between baseline CrCl and toxicity …

Association Of Second-Generation Antiandrogens With Cognitive And Functional Toxic Effects In Randomized Clinical Trials: A Systematic Review And Meta-Analysis, Malgorzata K Nowakowska, Rachel M Ortega, Mackenzie R Wehner, Kevin T Nead

Faculty, Staff and Student Publications

Importance: The use of second-generation antiandrogens (AAs) in the treatment of prostate cancer is increasing. Retrospective evidence suggests an association between second-generation AAs and adverse cognitive and functional outcomes, but further data from prospective trials are needed.

Objective: To examine whether evidence from randomized clinical trials (RCTs) in prostate cancer supports an association between second-generation AAs and cognitive or functional toxic effects.

Data sources: PubMed, EMBASE, and Scopus (inception to September 12, 2022).

Study selection: Randomized clinical trials of second-generation AAs (abiraterone, apalutamide, darolutamide, or enzalutamide) among individuals with prostate cancer that reported cognitive toxic effects, asthenic toxic effects (eg, …

Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome, Melissa R Hines, Tristan E Knight, Kevin O Mcnerney, Mark B Leick, Tania Jain, Sairah Ahmed, Matthew J Frigault, Joshua A Hill, Michael D Jain, William T Johnson, Yi Lin, Kris M Mahadeo, Gabriela M Maron, Rebecca A Marsh, Sattva S Neelapu, Sarah Nikiforow, Amanda K Ombrello, Nirav N Shah, Aimee C Talleur, David Turicek, Anant Vatsayan, Sandy W Wong, Marcela V Maus, Krishna V Komanduri, Nancy Berliner, Jan-Inge Henter, Miguel-Angel Perales, Noelle V Frey, David T Teachey, Matthew J Frank, Nirali N Shah

Faculty, Staff and Student Publications

T cell-mediated hyperinflammatory responses, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), are now well-established toxicities of chimeric antigen receptor (CAR) T cell therapy. As the field of CAR T cells advances, however, there is increasing recognition that hemophagocytic lymphohistiocytosis (HLH)-like toxicities following CAR T cell infusion are occurring broadly across patient populations and CAR T cell constructs. Importantly, these HLH-like toxicities are often not as directly associated with CRS and/or its severity as initially described. This emergent toxicity, however ill-defined, is associated with life-threatening complications, creating an urgent need for improved identification and optimal …

Biallelic Variants In Cript Cause A Rothmund-Thomson-Like Syndrome With Increased Cellular Senescence, Luisa Averdunk, Maxim A Huetzen, Daniel Moreno-Andrés, Reinhard Kalb, Shane Mckee, Tzung-Chien Hsieh, Annette Seibt, Marten Schouwink, Seema Lalani, Eissa Ali Faqeih, Theresa Brunet, Peter Boor, Kornelia Neveling, Alexander Hoischen, Barbara Hildebrandt, Elisabeth Graf, Linchao Lu, Weidong Jin, Joerg Schaper, Jamal A Omer, Tanguy Demaret, Nicole Fleischer, Detlev Schindler, Peter Krawitz, Ertan Mayatepek, Dagmar Wieczorek, Lisa L Wang, Wolfram Antonin, Ron D Jachimowicz, Verena Von Felbert, Felix Distelmaier

Faculty, Staff and Students Publications

Purpose: Rothmund-Thomson syndrome (RTS) is characterized by poikiloderma, sparse hair, small stature, skeletal defects, cancer, and cataracts, resembling features of premature aging. RECQL4 and ANAPC1 are the 2 known disease genes associated with RTS in >70% of cases. We describe RTS-like features in 5 individuals with biallelic variants in CRIPT (OMIM 615789).

Methods: Two newly identified and 4 published individuals with CRIPT variants were systematically compared with those with RTS using clinical data, computational analysis of photographs, histologic analysis of skin, and cellular studies on fibroblasts.

Results: All CRIPT individuals fulfilled the diagnostic criteria for RTS and additionally had neurodevelopmental …

De Novo Variants In Cnot9 Cause A Neurodevelopmental Disorder With Or Without Epilepsy, Lydia Von Wintzingerode, Bruria Ben-Zeev, Claudia Cesario, Katie M Chan, Christel Depienne, Orly Elpeleg, Maria Iascone, Whitley V Kelley, Marie-Cécile Nassogne, Marcello Niceta, Lidia Pezzani, Nils Rahner, Nicole Revencu, Mir Reza Bekheirnia, Teresa Santiago-Sim, Marco Tartaglia, Michelle L Thompson, Marina Trivisano, Julia Hentschel, Heinrich Sticht, Rami Abou Jamra, Henry Oppermann

Faculty, Staff and Students Publications

Purpose: The study aimed to clinically and molecularly characterize the neurodevelopmental disorder associated with heterozygous de novo variants in CNOT9.

Methods: Individuals were clinically examined. Variants were identified using exome or genome sequencing. These variants were evaluated using in silico predictions, and their functional relevance was further assessed by molecular models and research in the literature. The variants have been classified according to the criteria of the American College of Medical Genetics.

Results: We report on 7 individuals carrying de novo missense variants in CNOT9, p.(Arg46Gly), p.(Pro131Leu), and p.(Arg227His), and, recurrent in 4 unrelated individuals, p.(Arg292Trp). All affected persons have …

Co-Targeting Fasn And Mtor Suppresses Uveal Melanoma Growth, Anna Han, Dzmitry Mukha, Vivian Chua, Timothy J Purwin, Manoela Tiago, Bhavik Modasia, Usman Baqai, Jenna L Aumiller, Nelisa Bechtel, Emily Hunter, Meggie Danielson, Mizue Terai, Philip B Wedegaertner, Takami Sato, Solange Landreville, Michael A Davies, Stefan Kurtenbach, J William Harbour, Zachary T Schug, Andrew E Aplin

Faculty, Staff and Student Publications

Uveal melanoma (UM) displays a high frequency of metastasis; however, effective therapies for metastatic UM are limited. Identifying unique metabolic features of UM may provide a potential targeting strategy. A lipid metabolism protein expression signature was induced in a normal choroidal melanocyte (NCM) line transduced with GNAQ (Q209L), a driver in UM growth and development. Consistently, UM cells expressed elevated levels of fatty acid synthase (FASN) compared to NCMs. FASN upregulation was associated with increased mammalian target of rapamycin (mTOR) activation and sterol regulatory element-binding protein 1 (SREBP1) levels. FASN and mTOR inhibitors alone significantly reduced UM cell growth. Concurrent …

A Phase I Study Of Milademetan (Ds3032b) In Combination With Low Dose Cytarabine With Or Without Venetoclax In Acute Myeloid Leukemia: Clinical Safety, Efficacy, And Correlative Analysis, Jayastu Senapati, Muharrem Muftuoglu, Jo Ishizawa, Hussein A Abbas, Sanam Loghavi, Gautam Borthakur, Musa Yilmaz, Ghayas C Issa, Samuel I Dara, Mahesh Basyal, Li Li, Kiran Naqvi, Rasoul Pourebrahim, Elias J Jabbour, Steven M Kornblau, Nicholas J Short, Naveen Pemmaraju, Guillermo Garcia-Manero, Farhad Ravandi, Joseph Khoury, Naval Daver, Hagop M Kantarjian, Michael Andreeff, Courtney D Dinardo

Faculty, Staff and Student Publications

In TP53 wild-type acute myeloid leukemia (AML), inhibition of MDM2 can enhance p53 protein expression and potentiate leukemic cell apoptosis. MDM2 inhibitor (MDM2i) monotherapy in AML has shown modest responses in clinical trials but combining options of MDM2i with other potent AML-directed agents like cytarabine and venetoclax could improve its efficacy. We conducted a phase I clinical trial (NCT03634228) to study the safety and efficacy of milademetan (an MDM2i) with low-dose cytarabine (LDAC)±venetoclax in adult patients with relapsed refractory (R/R) or newly diagnosed (ND; unfit) TP53 wild-type AML and performed comprehensive CyTOF analyses to interrogate multiple signaling pathways, …

Lateral Septum As A Melanocortin Downstream Site In Obesity Development, Yuanzhong Xu, Zhiying Jiang, Hongli Li, Jing Cai, Yanyan Jiang, Joshua Ortiz-Guzman, Yong Xu, Benjamin R Arenkiel, Qingchun Tong

Duncan NRI Faculty and Staff Publications

No abstract provided.

Nanoparticle-Enhanced Proton Beam Immunoradiotherapy Drives Immune Activation And Durable Tumor Rejection, Yun Hu, Sébastien Paris, Narayan Sahoo, Genevieve Bertolet, Qi Wang, Qianxia Wang, Hampartsoum B Barsoumian, Jordan Da Silva, Ailing Huang, Denaha J Doss, David P Pollock, Ethan Hsu, Nanez Selene, Claudia S Kettlun Leyton, Tiffany A Voss, Fatemeh Masrorpour, Shonik Ganjoo, Carola Leuschner, Jordan T Pietz, Nahum Puebla-Osorio, Saumil Gandhi, Quynh-Nhu Nguyen, Jing Wang, Maria Angelica Cortez, James W Welsh

Faculty, Staff and Student Publications

The combination of radiation therapy (RT) and immunotherapy has emerged as a promising treatment option in oncology. Historically, x-ray radiation (XRT) has been the most commonly used form of RT. However, proton beam therapy (PBT) is gaining recognition as a viable alternative, as it has been shown to produce similar outcomes to XRT while minimizing off-target effects. The effects of PBT on the antitumor immune response have only just begun to be described, and to our knowledge no studies to date have examined the effect of PBT as part of a combinatorial immunoradiotherapeutic strategy. Here, using a 2-tumor model of …

Long-Term Outcomes And Molecular Correlates Of Sotorasib Efficacy In Patients With Pretreated Kras G12c-Mutated Non–Small-Cell Lung Cancer: 2-Year Analysis Of Codebreak 100, Grace K Dy, Ramaswamy Govindan, Vamsidhar Velcheti, Gerald S Falchook, Antoine Italiano, Jürgen Wolf, Adrian G Sacher, Toshiaki Takahashi, Suresh S Ramalingam, Christophe Dooms, Dong-Wan Kim, Alfredo Addeo, Jayesh Desai, Martin Schuler, Pascale Tomasini, David S Hong, Piro Lito, Qui Tran, Simon Jones, Abraham Anderson, Antreas Hindoyan, Wendy Snyder, Ferdinandos Skoulidis, Bob T Li

Faculty, Staff and Student Publications

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.

In the longest follow-up, to our knowledge, for a KRAS^G12C inhibitor, we assessed the long-term efficacy, safety, and biomarkers of sotorasib in patients with KRAS G12C-mutated advanced non–small-cell lung cancer (NSCLC) from the CodeBreaK 100 clinical …

Wdr5 Facilitates Recruitment Of N-Myc To Conserved Wdr5 Gene Targets In Neuroblastoma Cell Lines, Leigh A Bumpous, Kylie C Moe, Jing Wang, Logan A Carver, Alexandria G Williams, Alexander S Romer, Jesse D Scobee, Jack N Maxwell, Cheyenne A Jones, Dai H Chung, William P Tansey, Qi Liu, April M Weissmiller

Faculty, Staff and Student Publications

Collectively, the MYC family of oncoprotein transcription factors is overexpressed in more than half of all malignancies. The ability of MYC proteins to access chromatin is fundamental to their role in promoting oncogenic gene expression programs in cancer and this function depends on MYC-cofactor interactions. One such cofactor is the chromatin regulator WDR5, which in models of Burkitt lymphoma facilitates recruitment of the c-MYC protein to chromatin at genes associated with protein synthesis, allowing for tumor progression and maintenance. However, beyond Burkitt lymphoma, it is unknown whether these observations extend to other cancers or MYC family members, and whether WDR5 …

Aging Fly Cell Atlas Identifies Exhaustive Aging Features At Cellular Resolution, Tzu-Chiao Lu, Maria Brbić, Ye-Jin Park, Tyler Jackson, Jiaye Chen, Sai Saroja Kolluru, Yanyan Qi, Nadja Sandra Katheder, Xiaoyu Tracy Cai, Seungjae Lee, Yen-Chung Chen, Niccole Auld, Chung-Yi Liang, Sophia H Ding, Doug Welsch, Samuel D'Souza, Angela Oliveira Pisco, Robert C Jones, Jure Leskovec, Eric C Lai, Hugo J Bellen, Liqun Luo, Heinrich Jasper, Stephen R Quake, Hongjie Li

Duncan NRI Faculty and Staff Publications

Aging is characterized by a decline in tissue function, but the underlying changes at cellular resolution across the organism remain unclear. Here, we present the Aging Fly Cell Atlas, a single-nucleus transcriptomic map of the whole aging Drosophila. We characterize 163 distinct cell types and perform an in-depth analysis of changes in tissue cell composition, gene expression, and cell identities. We further develop aging clock models to predict the fly age and show that ribosomal gene expression is a conserved predictive factor for age. Combining all aging features, we find unique cell type-specific aging patterns. This atlas provides a …

Loss Of Ampkα2 Promotes Melanoma Tumor Growth And Brain Metastasis, Ping Yuan, Da Teng, Evelyn De Groot, Man Li, Sebastian Trousil, Che-Hung Shen, Jason Roszik, Michael A Davies, Y N Vashisht Gopal, Bin Zheng

Faculty, Staff and Student Publications

AMP-activated protein kinase (AMPK) is a critical cellular energy sensor at the interface of metabolism and cancer. However, the role of AMPK in carcinogenesis remains unclear. Here, through analysis of the TCGA melanoma dataset, we found that PRKAA2 gene that encodes the α2 subunit of AMPK is mutated in ∼9% of cutaneous melanomas, and these mutations tend to co-occur with NF1 mutations. Knockout of AMPKα2 promoted anchorage-independent growth of NF1-mutant melanoma cells, whereas ectopic expression of AMPKα2 inhibited their growth in soft agar assays. Moreover, loss of AMPKα2 accelerated tumor growth of NF1-mutant melanoma and enhanced their brain …

Poly(A)-Binding Protein Is An Ataxin-2 Chaperone That Regulates Biomolecular Condensates, Steven Boeynaems, Yanniv Dorone, Yanrong Zhuang, Victoria Shabardina, Guozhong Huang, Anca Marian, Garam Kim, Anushka Sanyal, Nesli-Ece Şen, Daniel Griffith, Roberto Docampo, Keren Lasker, Iñaki Ruiz-Trillo, Georg Auburger, Alex S Holehouse, Edor Kabashi, Yi Lin, Aaron D Gitler

Duncan NRI Faculty and Staff Publications

Biomolecular condensation underlies the biogenesis of an expanding array of membraneless assemblies, including stress granules (SGs) which form under a variety of cellular stresses. Advances have been made in understanding the molecular grammar of a few scaffold proteins that make up these phases, but how the partitioning of hundreds of SG proteins is regulated remains largely unresolved. While investigating the rules that govern the condensation of ataxin-2, a SG protein implicated in neurodegenerative disease, we unexpectedly identified a short 14aa sequence that acts as a condensation switch and is conserved across the eukaryote lineage. We identify poly(A)-binding proteins as unconventional …

Extracellular Rna Sensing Mediates Inflammation And Organ Injury In A Murine Model Of Polytrauma, Andrew O Suen, Fengqian Chen, Sheng Wang, Ziyi Li, Jing Zhu, Yang Yang, Olivia Conn, Kerri Lopez, Ping Cui, Laurence Wechsler, Alan Cross, Gary Fiskum, Rosemary Kozar, Peter Hu, Catriona Miller, Lin Zou, Brittney Williams, Wei Chao

Faculty, Staff and Student Publications

Severe traumatic injury leads to marked systemic inflammation and multiorgan injury. Endogenous drivers such as extracellular nucleic acid may play a role in mediating innate immune response and the downstream pathogenesis. Here, we explored the role of plasma extracellular RNA (exRNA) and its sensing mechanism in inflammation and organ injury in a murine model of polytrauma. We found that severe polytrauma—bone fracture, muscle crush injury, and bowel ischemia—induced a marked increase in plasma exRNA, systemic inflammation, and multiorgan injury in mice. Plasma RNA profiling with RNA sequencing in mice and humans revealed a dominant presence of miRNAs and marked differential …

The Insulin Receptor Regulates The Persistence Of Mechanical Nociceptive Sensitization In Flies And Mice, Yan Wang, Roger Lopez-Bellido, Xiaojiao Huo, Annemieke Kavelaars, Michael J Galko

Faculty, Staff and Student Publications

Early phase diabetes is often accompanied by pain sensitization. In Drosophila, the insulin receptor (InR) regulates the persistence of injury-induced thermal nociceptive sensitization. Whether Drosophila InR also regulates the persistence of mechanical nociceptive sensitization remains unclear. Mice with a sensory neuron deletion of the insulin receptor (Insr) show normal nociceptive baselines; however, it is uncertain whether deletion of Insr in nociceptive sensory neurons leads to persistent nociceptive hypersensitivity. In this study, we used fly and mouse nociceptive sensitization models to address these questions. In flies, InR mutants and larvae with sensory neuron-specific expression of RNAi transgenes targeting InR exhibited persistent …

Association Between Bariatric Surgery And Outcomes In Chronic Myeloid Leukemia, Fadi G Haddad, Hagop M Kantarjian, Aram Bidikian, Elias J Jabbour, Nicholas J Short, Jing Ning, Lianchun Xiao, Naveen Pemmaraju, Courtney D Dinardo, Tapan M Kadia, Kayleigh R Marx, Guillermo Garcia-Manero, Farhad Ravandi, Koji Sasaki, Ghayas C Issa

Faculty, Staff and Student Publications

Background: Bariatric surgery is the most effective weight loss intervention. However, it can also decrease the bioavailability of oral medications. Tyrosine kinase inhibitors, the mainstay treatment for chronic myeloid leukemia (CML), are the most successful example of an oral targeted therapy. The impact of bariatric surgery on CML outcomes is unknown.

Methods: In a retrospective analysis, we screened 652 patients with CML and identified 22 with prior bariatric surgery, and compared their outcomes to a matched cohort of 44 patients with no prior bariatric surgery.

Results: The rate of early molecular response (3-month BCR::ABL1 < 10% International Scale) was lower in the bariatric surgery group compared with the control group (68% vs. 91%; p = .05), with longer median times to achieve complete cytogenetic (6 vs. 3 months; p = .001) or major molecular responses (12 vs. 6 months; p = .001). Bariatric surgery was associated with inferior event-free survival (5-year, 60% vs. 77%; p = .004) and failure-free survival (5-year, 32% vs. 63%; p < .0001). In a multivariate analysis, bariatric surgery was the only independent predictor for the risk of treatment failure (hazard ratio, 9.40; 95% CI, 2.71-32.55; p = .0004) or event-free survival (hazard ratio, 4.24; 95% CI, 1.67-12.23; p = .008).

Conclusions: Bariatric surgery is associated with …

A Comparison Of Two Approaches To Dynamic Prediction: Joint Modeling And Landmark Modeling, Wenhao Li, Liang Li, Brad C Astor

Faculty, Staff and Student Publications

Joint modeling and landmark modeling are two mainstream approaches to dynamic prediction in longitudinal studies, that is, the prediction of a clinical event using longitudinally measured predictor variables available up to the time of prediction. It is an important research question to the methodological research field and also to practical users to understand which approach can produce more accurate prediction. There were few previous studies on this topic, and the majority of results seemed to favor joint modeling. However, these studies were conducted in scenarios where the data were simulated from the joint models, partly due to the widely recognized …

Ohsv-P10 Reduces Glioma Stem Cell Enrichment After Oncolytic Hsv Therapy, Upasana Sahu, Matthew P Mullarkey, Guangsheng Pei, Zhongming Zhao, Bangxing Hong, Balveen Kaur

Faculty, Staff and Student Publications

Longstanding evidence implicate glioma stem-like cells as the main drivers contributing toward glioblastoma (GBM) therapy resistance and tumor recurrence. Although oncolytic herpes simplex virus (oHSV) viral therapy is a promising biological therapy recently approved for melanoma (in the United States and Europe) and GBM (in Japan); however, the impact of this therapy on GBM stem-like cells (GSCs) is understudied. Here we show that post-oHSV virotherapy activated AKT signaling results in an enrichment of GSC signatures in glioma, which mimics the enrichment in GSC observed after radiation treatment. We also uncovered that a second-generation oncolytic virus armed with PTEN-L (oHSV-P10) decreases …

Hematopoietic Progenitor Kinase 1 Inhibits The Development And Progression Of Pancreatic Intraepithelial Neoplasia, Hua Wang, Rohan Moniruzzaman, Lei Li, Baoan Ji, Yi Liu, Xiangsheng Zuo, Reza Abbasgholizadeh, Jun Zhao, Guangchao Liu, Ruiqi Wang, Hongli Tang, Ryan Sun, Xiaoping Su, Tse-Hua Tan, Anirban Maitra, Huamin Wang

Faculty, Staff and Student Publications

Ras plays an essential role in the development of acinar-to-ductal metaplasia (ADM) and pancreatic ductal adenocarcinoma (PDAC). However, mutant Kras is an inefficient driver for PDAC development. The mechanisms of the switching from low Ras activity to high Ras activity that are required for development and progression of pancreatic intraepithelial neoplasias (PanINs) are unclear. In this study, we found that hematopoietic progenitor kinase 1 (HPK1) was upregulated during pancreatic injury and ADM. HPK1 interacted with the SH3 domain and phosphorylated Ras GTPase-activating protein (RasGAP) and upregulated RasGAP activity. Using transgenic mouse models of HPK1 or M46, a kinase-dead mutant of …

Early Mortality In Acute Myeloid Leukemia With Kmt2a Rearrangement Is Associated With High Risk Of Bleeding And Disseminated Intravascular Coagulation, Daniel Nguyen, Hagop M Kantarjian, Nicholas J Short, Wei Qiao, Jing Ning, Branko Cuglievan, Naval G Daver, Courtney D Dinardo, Elias J Jabbour, Tapan M Kadia, Gautam Borthakur, Guillermo Garcia-Manero, Marina Y Konopleva, Michael Andreeff, Farhad Ravandi-Kashani, Koji Sasaki, Ghayas C Issa

Faculty, Staff and Student Publications

Background: Acute myeloid leukemia (AML) with rearrangement of lysine methyltransferase 2a gene (KMT2Ar) is characterized by chemotherapy resistance and high rates of relapse. However, additional causes of treatment failure or early mortality have not been well-defined in this entity.

Methods: In a retrospective analysis, causes and rates of early mortality following induction treatment were compared between a cohort of adults with KMT2Ar AML (N = 172) and an age-matched cohort of patients with normal karyotype AML (N = 522).

Results: The 60-day mortality in patients with KMT2Ar AML was 15% compared with 7% with normal karyotype (p = .04). We …

Eganelisib, A First-In-Class Pi3kγ Inhibitor, In Patients With Advanced Solid Tumors: Results Of The Phase 1/1b Mario-1 Trial, David S Hong, Michael Postow, Bartosz Chmielowski, Ryan Sullivan, Amita Patnaik, Ezra E W Cohen, Geoffrey Shapiro, Conor Steuer, Martin Gutierrez, Heather Yeckes-Rodin, Robert Ilaria, Brenda O'Connell, Joanna Peng, Guangbin Peng, Nora Zizlsperger, Anthony Tolcher, Jedd D Wolchok

Faculty, Staff and Student Publications

Purpose: Eganelisib (IPI-549) is a first-in-class, orally administered, highly selective PI3Kγ inhibitor with antitumor activity alone and in combination with programmed cell death protein 1/ligand 1 (PD-1/PD-L1) inhibitors in preclinical studies. This phase 1/1b first-in-human, MAcrophage Reprogramming in Immuno-Oncology-1 (NCT02637531) study evaluated the safety and tolerability of once-daily eganelisib as monotherapy and in combination with nivolumab in patients with solid tumors.

Patients and methods: Dose-escalation cohorts received eganelisib 10-60 mg as monotherapy (n = 39) and 20-40 mg when combined with nivolumab (n = 180). Primary endpoints included incidence of dose-limiting toxicities (DLT) and adverse events (AE).

Results: …

Correction: Dual Inhibition Of Igf-Ir And Alk As An Effective Strategy To Eradicate Npm-Alk+ T-Cell Lymphoma, Bhawana George, Suraj Konnath George, Wenyu Shi, Abedul Haque, Ping Shi, Ghazaleh Eskandari, Magnus Axelson, Olle Larsson, Ahmed O Kaseb, Hesham M Amin

Faculty, Staff and Student Publications

No abstract provided.

Need For Risk Adjustment In Comparative Effectiveness And Cost-Effectiveness Studies In R/R Follicular Lymphoma, John Gribben, M Lia Palomba, Anik R Patel, Myrna Nahas, Sattva S Neelapu

Faculty, Staff and Student Publications

No abstract provided.

Asct Vs Cart For Patients With Relapsed Lbcl In Pr: Role Of Tmtv, Paolo Strati, Oren Pasvolsky, Lei Feng, Guofan Xu, Sanjit O Tewari, Jaimole Varghese, Karla Ow, Minifrida Santiago, Ajlan Al Zaki, Andrew Jallouk, Sattva S Neelapu, Partow Kebriaei, Elizabeth J Shpall, Sairah Ahmed

Faculty, Staff and Student Publications

No abstract provided.

Leveraging Mid-Infrared Spectroscopic Imaging And Deep Learning For Tissue Subtype Classification In Ovarian Cancer, Chalapathi Charan Gajjela, Matthew Brun, Rupali Mankar, Sara Corvigno, Noah Kennedy, Yanping Zhong, Jinsong Liu, Anil K Sood, David Mayerich, Sebastian Berisha, Rohith Reddy

Faculty, Staff and Student Publications

Mid-infrared spectroscopic imaging (MIRSI) is an emerging class of label-free techniques being leveraged for digital histopathology. Modern histopathologic identification of ovarian cancer involves tissue staining followed by morphological pattern recognition. This process is time-consuming and subjective and requires extensive expertise. This paper presents the first label-free, quantitative, and automated histological recognition of ovarian tissue subtypes using a new MIRSI technique. This optical photothermal infrared (O-PTIR) imaging technique provides a 10× enhancement in spatial resolution relative to prior instruments. It enables sub-cellular spectroscopic investigation of tissue at biochemically important fingerprint wavelengths. We demonstrate that the enhanced resolution of sub-cellular features, combined …

Clinical Significance And Biology Of Circulating Tumor Dna In High-Risk Early-Stage Her2-Negative Breast Cancer Receiving Neoadjuvant Chemotherapy, Mark Jesus M Magbanua, Lamorna Brown Swigart, Ziad Ahmed, Rosalyn W Sayaman, Derrick Renner, Ekaterina Kalashnikova, Gillian L Hirst, Christina Yau, Denise M Wolf, Wen Li, Amy L Delson, Smita Asare, Minetta C Liu, Kathy Albain, A Jo Chien, Andres Forero-Torres, Claudine Isaacs, Rita Nanda, Debu Tripathy, Angel Rodriguez, Himanshu Sethi, Alexey Aleshin, Matthew Rabinowitz, Jane Perlmutter, W Fraser Symmans, Douglas Yee, Nola M Hylton, Laura J Esserman, Angela M Demichele, Hope S Rugo, Laura J Van 'T Veer

Faculty, Staff and Student Publications

Circulating tumor DNA (ctDNA) analysis may improve early-stage breast cancer treatment via non-invasive tumor burden assessment. To investigate subtype-specific differences in the clinical significance and biology of ctDNA shedding, we perform serial personalized ctDNA analysis in hormone receptor (HR)-positive/HER2-negative breast cancer and triple-negative breast cancer (TNBC) patients receiving neoadjuvant chemotherapy (NAC) in the I-SPY2 trial. ctDNA positivity rates before, during, and after NAC are higher in TNBC than in HR-positive/HER2-negative breast cancer patients. Early clearance of ctDNA 3 weeks after treatment initiation predicts a favorable response to NAC in TNBC only. Whereas ctDNA positivity associates with reduced distant recurrence-free survival …

Whole Genome Analysis For 163 Grnas In Cas9-Edited Mice Reveals Minimal Off-Target Activity, Kevin A Peterson, Sam Khalouei, Nour Hanafi, Joshua A Wood, Denise G Lanza, Lauri G Lintott, Brandon J Willis, John R Seavitt, Robert E Braun, Mary E Dickinson, Jacqueline K White, K C Kent Lloyd, Jason D Heaney, Stephen A Murray, Arun Ramani, Lauryl M J Nutter

Faculty, Staff and Students Publications

Genome editing with CRISPR-associated (Cas) proteins holds exceptional promise for "correcting" variants causing genetic disease. To realize this promise, off-target genomic changes cannot occur during the editing process. Here, we use whole genome sequencing to compare the genomes of 50 Cas9-edited founder mice to 28 untreated control mice to assess the occurrence of S. pyogenes Cas9-induced off-target mutagenesis. Computational analysis of whole-genome sequencing data detects 26 unique sequence variants at 23 predicted off-target sites for 18/163 guides used. While computationally detected variants are identified in 30% (15/50) of Cas9 gene-edited founder animals, only 38% (10/26) of the variants in 8/15 …