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  • 1
    Online Resource
    Online Resource
    Elsevier BV ; 2021
    In:  European Urology Open Science Vol. 31 ( 2021-09), p. S7-
    In: European Urology Open Science, Elsevier BV, Vol. 31 ( 2021-09), p. S7-
    Type of Medium: Online Resource
    ISSN: 2666-1683
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
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  • 2
    Online Resource
    Online Resource
    Elsevier BV ; 2021
    In:  European Urology Open Science Vol. 31 ( 2021-09), p. S27-
    In: European Urology Open Science, Elsevier BV, Vol. 31 ( 2021-09), p. S27-
    Type of Medium: Online Resource
    ISSN: 2666-1683
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 3040546-4
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  • 3
    In: Nature, Springer Science and Business Media LLC, Vol. 629, No. 8013 ( 2024-05-23), p. 927-936
    Abstract: Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations 1,2 . RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS and NRAS, with affinity for both mutant and wild-type variants 3 . More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS 4 . Here we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumour activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumour versus normal tissues. Treated tumours exhibited waves of apoptosis along with sustained proliferative arrest, whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. In the autochthonous KPC mouse model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance.
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2024
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    detail.hit.zdb_id: 1413423-8
    SSG: 11
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  • 4
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 22_Supplement ( 2022-11-15), p. A052-A052
    Abstract: Transcriptional states in pancreatic cancer can stratify patients by response to chemotherapy and clinical outcomes. These include the classical and basal-like states as well as a newly identified neural-like progenitor (NRP) state, which we have previously found to be enriched in primary patient tumors treated with neoadjuvant chemotherapy and radiotherapy. While several transcription factor drivers of classical and basal-like identity have been described, key regulators of the NRP state are unknown. Through in silico approaches, we identified candidate transcription factors of the NRP state, including GLIS3, a Krüppel-like zinc finger protein that mediates neuroendocrine fate during pancreatic development and differentiation of human embryonic stem cells into posterior neural progenitor cells. Our understanding of biologic and clinically-relevant attributes of transcriptional cell states remains limited by state-specific biases in various preclinical models. Existing human cell lines maintained as two-dimensional cultures tend to preferentially represent the basal-like state, whereas human three-dimensional organoid models grown in standard culture conditions best reflect the classical state. These phenotypes are therefore impacted by culture conditions as well as underlying genetic features. Furthermore, most murine pancreatic cancer models do not fully reflect the classical vs. basal-like state heterogeneity observed in humans. To enable systematic study of the classical, basal-like and NRP phenotypes, we developed isogenic KP (KrasG12D/+;Trp53FL/FL) murine organoids with a germline dCas9-VPR system to enable facile overexpression of state-specific transcription factors through CRISPR activation approaches. Quantitative PCR, RNA-sequencing, and proteomics confirmed Gata6, deltaN Trp63, and Glis3 as drivers of classical, basal-like, and NRP identity, respectively. DeltaN Trp63 organoids were further differentiated by loss of luminal morphology. Pairwise comparisons of global transcriptional alterations suggest the greatest similarities between the Gata6- and Glis3-overexpressed models, which is consistent with enhanced associations between classical and NRP states in patient tumors. Finally, although basal-like and NRP states are associated with poorer response to multi-agent chemotherapy, state-specific therapeutic sensitivities to other treatments remain incompletely defined. We therefore performed drug sensitivity assays with a panel of targeted therapies and unveiled state-specific sensitivities. These data were corroborated by drug sensitivity profiling of human patient-derived organoids and cell lines. Taken together, these results suggest a framework for defining cell state-specific vulnerabilities that may aid in stratifying and treating pancreatic cancer patients with new therapies. Citation Format: Jimmy A. Guo, Jennifer Su, Ananya Jambhale, Julien Dilly, Connor J. Hennessey, Carina Shiau, Patrick Yu, Steven Wang, Junning Wang, Laleh Abbassi, James Neiswender, Tate Bertea, Annan Yang, Qijia Yu, Peter Westcott, Jason Schenkel, Daniel Y. Kim, Hannah I. Hoffman, Grissel Cervantes Jaramillo, Giselle A. Uribe, Westley W. Wu, Arnav Mehta, David Ting, Julian A. Pacheco, Amy Deik, Clary Clish, Francisca Vazquez, Brian Wolpin, Aviv Regev, William A. Freed-Pastor, Joseph D. Mancias, Tyler Jacks, William L. Hwang, Andrew J. Aguirre. Systematic dissection of transcriptional states in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A052.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 5
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 22_Supplement ( 2022-11-15), p. A075-A075
    Abstract: Pancreatic ductal adenocarcinomas (PDAC) depend on autophagy for survival; however, the metabolic substrates that autophagy provides to drive PDAC progression are unclear. Ferritin, the cellular iron storage complex, is targeted for lysosomal degradation (ferritinophagy) by the selective autophagy adaptor Nuclear receptor coactivator 4 (NCOA4), resulting in release of iron for cellular utilization. Using patient-derived and genetically engineered murine models of PDAC we now demonstrate that ferritinophagy is upregulated in PDAC to sustain iron availability thereby promoting tumor progression. Mass spectrometry-based quantitative proteomics reveals that ferritinophagy fuels iron-sulfur cluster protein synthesis to support mitochondrial homeostasis. Targeting NCOA4 leads to tumor growth delay and prolonged survival but with development of compensatory iron acquisition pathways. Finally, enhanced ferritinophagy accelerates PDAC tumorigenesis, and an elevated ferritinophagy expression signature predicts for poor prognosis in PDAC patients. Together, our data reveal that maintenance of iron homeostasis is a critical function of PDAC autophagy, and we define NCOA4-mediated ferritinophagy as a therapeutic target in PDAC. Citation Format: Naiara Santana-Codina, Huan Zhang, Maria Quiles del Rey, Kevin S. Kapner, Ajami Gikandi, Callum Malcolm, Clara Poupault, Miljan Kuljanin, Kristen John, Douglas E. Biancur, Brandon Chen, Nupur Das, Kristen Lowder, Connor J. Hennessey, Wesley Huang, Annan Yang, Yatrik M. Shah, Jonathan A. Nowak, Andrew J. Aguirre, Joseph D. Mancias. NCOA4-mediated ferritinophagy is a pancreatic cancer dependency via maintenance of iron bioavailability for iron-sulfur cluster proteins [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A075.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2036785-5
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  • 6
    Online Resource
    Online Resource
    Elsevier BV ; 2022
    In:  Journal of the American College of Cardiology Vol. 79, No. 6 ( 2022-02), p. 609-613
    In: Journal of the American College of Cardiology, Elsevier BV, Vol. 79, No. 6 ( 2022-02), p. 609-613
    Type of Medium: Online Resource
    ISSN: 0735-1097
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    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
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  • 7
    In: Blood, American Society of Hematology, Vol. 142, No. Supplement 1 ( 2023-11-02), p. 255-255
    Abstract: Background: CAR-T cell therapy has transformed treatment of hematologic malignancies but is complex and challenging to convey to patients. Educational video interventions are efficacious for improving patient knowledge about cancer therapeutics and informing their care preferences; yet, no educational videos have been evaluated in CAR-T. Methods: We conducted a randomized controlled trial comparing an educational video versus usual care in adults ( & gt;18 years) with hematologic malignancies receiving CAR-T at Massachusetts General Hospital. Intervention participants watched a 13-minute video depicting how CAR-T works, logistics, toxicities, prognosis, recovery, and approaches to deal with prognostic uncertainty. Participants were permitted to watch the video a single time without interruption and were not given any further access or exposure to the video. The educational video arm also received usual clinical care. At our institution usual care includes a verbal discussion about CAR-T with a physician and nurse navigator along with written documentation about CAR-T. The primary outcome was feasibility ( & gt;=60% enrollment rate). Secondary outcomes included acceptability ( & gt;=80% reporting comfort with the video), patients' knowledge about CAR-T (10-item test), and self-efficacy (Communication and Attitudinal Self-Efficacy Scale-Cancer), decision satisfaction (Decision Conflict Scale), psychological distress (Hospital Anxiety and Depression Scale), and preference for CAR-T. Given the pilot nature of this study, we determined Cohen's d effect sizes for differences in knowledge, self-efficacy, decision satisfaction, anxiety, and depression between both groups at the 1 week and 1 month timepoints, with Cohen's d effect sizes of 0.2, 0.5, and 0.8 denoting small, medium, and large effect sizes, respectively. Results: Eighty participants were randomly assigned to the video (N=40) and the usual care (N=40) arms. Among all participants, most were White (93%), male gender (68%), married or living with a partner (80%), and college educated (54%). The most common cancer diagnosis was non-Hodgkin lymphoma (74%), followed by multiple myeloma (24%) and acute lymphoblastic leukemia (3%) [Table 1] . The primary endpoint of feasibility was met, as we enrolled 79% (80/101) of eligible patients. The video was highly acceptable to patients: 91% (30/33) reported being very or somewhat comfortable watching the video, 90.9% (30/33) reported the video was very or somewhat helpful, and 94% (31/33) would definitely or probably recommend the video. At 1 week, video arm participants reported higher self-efficacy (mean difference [MD]=19.4, 95% confidence interval [CI] 7.5-31.4, Cohen's d 0.8) and decision satisfaction (MD=1.6, 95% CI [0.1-3.1], Cohen's d: 0.5) compared to usual care participants. At 1 week, both arms reported high preferences for CAR-T (video arm: 94% [33/35] ; usual care: 84% [27/32]). At 1 month, video arm participants reported higher self-efficacy (MD=9.2, 95% CI [-4.0-22.3] , Cohen's d: 0.3) and decision satisfaction (MD=2.5, 95% CI [0.7-4.2], Cohen's d: 0.7) and lower anxiety (MD= -0.9, 95% CI [-2.5-0.7] , Cohen's d: 0.3) compared to usual care participants (Table 2). Knowledge scores were high in both arms throughout all time points and were similar between groups at 1 week (MD=0.0, 95% CI [-0.7-0.7], Cohen's d 0.0) and 1 month (MD=0.1, 95% CI [-0.6-0.7] , Cohen's d: 0.1). Depression scores were similar between groups at 1 week (MD= -0.3, 95% CI [-2.0-1.3], Cohen's d: 0.1) and 1 month (MD= -0.3, 95% CI [-2.2-1.7] , Cohen's d: 0.1). Conclusions: We found that an educational video in patients with hematologic malignancies receiving CAR-T was feasible and highly acceptable to patients. We also demonstrated promising preliminary effects on self-efficacy, decision satisfaction, and anxiety. We identified only modest changes in knowledge scores, likely due to a ceiling effect from high knowledge scores at baseline. Our results highlight the potential utility of videos for improving the care delivery of patients receiving CAR-T and support a future large efficacy trial to definitively assess the impact of the video on patient-reported outcomes and care delivery.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2023
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  • 8
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 84, No. 2_Supplement ( 2024-01-16), p. A078-A078
    Abstract: Pancreatic ductal adenocarcinoma (PDAC), among the most lethal cancers with a 5-year survival rate of 11%, is a KRAS-driven disease. Studies have shown that a single glycine (G) to aspartic acid (D) substitution on codon 12 of KRAS protein (known as KRASG12D mutation) appears in 41% of all PDAC cases, highlighting the necessity of targeting KRASG12D as a therapeutic approach. MRTX1133, a recently developed potent, non-covalent, direct, and selective KRASG12D small molecule inhibitor demonstrates a high-affinity interaction with KRASG12D. Previous studies have shown striking efficacy of MRTX1133 on growth inhibition of mouse/human PDAC tumor cells carrying KRASG12D mutation in various in vivo and in vitro models, during short-term treatment. Here in our study, we investigated the efficacy of continuous long-term treatment with MRTX1133 in two different PDAC mouse models: KPC (a genetically engineered mouse model harboring a KRASG12D mutation) and its syngeneic orthotopic model. In both models, tumor sizes were detected by ultrasound imaging and after reaching 100-300 mm3 in volume, mice were enrolled in either MRTX1133 or vehicle treatment (30mg/kg, IP, BID). Tumor sizes were monitored by ultrasound regularly and the treatment continued until mice reached clinical endpoint. At endpoint, mice were sacrificed, and tumors were harvested for a series of downstream experiments. Our results showed that while, in both models, vehicle treated tumors grew aggressively and mice reached endpoint in average 6 days post treatment, drug treated tumors regressed rapidly and survival rate increased significantly to as late as 222 days post treatment in KPC model. However, in both models, drug treated tumors ultimately relapsed, developed resistance to the drug, and resulted in death. Further analysis of KPC mice ultrasound images evidenced that the relapsed tumors occurred at the same sites of the primary tumors. This suggests the possibility of relapsed tumors arising from the regrowth of the dormant residual cells from the primary tumors. Re-implantation of the resistant tumors either in the flank or pancreata of the new wildtype mice resulted in the formation of drug-resistant tumors in hosts. In addition, histopathology analysis of the tumor sections demonstrated a significant increase in the ratio of invasive PDAC to PanIN areas in the drug resistant tumors. Furthermore, multiplex immunofluorescence of both MRTX1133 resistant and vehicle treated tumors from KPC mice demonstrated co-expression of markers representing basal-like and classical PDAC subtypes. Moreover, flow cytometry analysis indicated an increase in the myeloid population of the resistant tumors comparing to the vehicle treated group. In the future directions, through applying a broad range of cellular and molecular experiments we will characterize the kinetics of KRAS inhibitor drug resistance and define possible combination therapy startegies to overcome drug resistance mechanisms. Citation Format: Laleh Abbassi, Jullien Dilly, Annan Yang, Giselle Uribe, Branden Parent, Connor Hennessey, Kevin Kapner, Alexander Jordan, Shatavisha Dasgupta, Micaela Morgado, Taimour Baslan, Li Qiang, Peter Winter, Seema Chugh, Alex Shalek, Ben Stanger, Srivastan Raghavan, Scott Lowe, Brian Wolpin, Stephanie Dougan, Jonathan Nowak, Andrew Aguirre. Response and resistance to KRAS inhibition in PDAC mouse models [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A078.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2024
    detail.hit.zdb_id: 2036785-5
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  • 9
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 84, No. 6_Supplement ( 2024-03-22), p. 1933-1933
    Abstract: KRAS is a major oncogenic driver in pancreatic ductal adenocarcinoma (PDAC) and is mutationally activated in approximately 90% of cases, with the glycine-to-aspartic acid substitution at position 12 (p.G12D) being the most prevalent alteration. Mutations in this oncogene have been associated with more aggressive disease and poorer outcomes and have remained “undruggable” for more than three decades. However, the recent development of mutant-specific small molecule inhibitors of KRAS has given hope for the treatment of this highly lethal and treatment-refractory malignancy. Here we evaluated the genomic and transcriptional mechanisms of resistance to MRTX1133, a first-in-class inhibitor of KRASG12D, in an autochthonous mouse model of PDAC. We leveraged single-nucleus RNA sequencing and whole-exome sequencing on 17 tumors from KPC mouse specimens (LSL-KrasG12D/+; LSL-Trp53R172H/+; p48-Cre) that were treated with either MRTX1133 or the vehicle, including 6 samples from mice that developed acquired resistance to KRASG12D inhibition. Our analysis has uncovered that resistance is multifaceted and characterized by both emergent genomic and transcriptional features. Genetically, resistant tumors harbored clonal and subclonal amplifications in the HIPPO pathway, cell cycle regulators, and ABC transporters. Transcriptionally, we employed non-negative matrix factorization and identified recurrent gene expression programs in resistant and vehicle samples. Using this approach, we uncovered the existence of an intermediate phenotype between classical and mesenchymal cell states that is enriched in tumors with evolved resistance to MRTX1133. In summary, our study provides a high-resolution genomic and transcriptional landscape of resistance to KRAS targeting in a preclinical in vivo model of PDAC, highlighting the complexity of treatment resistance and identifying various pathways and effectors that may serve as potential new targets for combination therapy. Citation Format: Julien Dilly, Laleh Abbassi, Connor J. Hennessey, Giselle A. Uribe, Brendan Parent, Annan Yang, Kevin S. Kapner, Ziyue Li, Kyle E. Evans, Shatavisha Dasgupta, Megan T. Hoffman, Li Qiang, Felix P. Hambitzer, Seema Chugh, Alex K. Shalek, Stephanie K. Dougan, Brian M. Wolpin, Jonathan A. Nowak, Srivatsan Raghavan, Peter S. Winter, Andrew J. Aguirre. Dissecting acquired resistance to KRASG12D inhibition in a mouse model of pancreatic ductal adenocarcinoma [abstract] . In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1933.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2024
    detail.hit.zdb_id: 2036785-5
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  • 10
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 6088-6088
    Abstract: The number of patients benefiting from precision cancer medicine (PCM) is very limited. The Cancer Dependency Map Initiative aims to dramatically accelerate PCM by systematically identifying the landscape of cancer vulnerabilities across all tumors. Genome-wide knockout screens have been performed in over 1000 cancer cell lines, but these have been sourced from historically derived models, leaving many cancers underrepresented. Advances have been made in model derivation by growing cells in 3D formats, such as organoids or spheroids. These models present an opportunity to screen new cancer types, but come with challenges that require a new pipeline. Here, we present a set of screens using a genome wide CAS12 library in organoid tumor models representing novel subtypes of pancreatic, esophageal, and gastric cancer, along with treatment-resistant breast, ovarian, and prostate cancer organoids. We show that genome-wide screening of these models is feasible and can be achieved with quality comparable to 2D cell lines. Our work uncovered a set of novel dependencies associated with cell-ECM interactions that have not previously been identified in 2D models. Our methods provide a framework for screening future patient derived 3D culture models and discovering vulnerabilities in new tumor types. Citation Format: James V. Neiswender, Lisa Brenan, Tate Bertea, Jimmy Guo, Ashley Anderson, Megan Wong, Zoe Posner, Kevin Kapner, Connor Hennessey, Sarah Wie, Isabella Boyle, Barbara De Kegel, Joshua Dempster, Yuen-Yi (Moony) Tseng, David Root, Andrew Aguirre, Francisca Vazquez. Charting new cancer dependencies with patient derived organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6088.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2036785-5
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