tbuckley/cabot-search huggingface dataset:
Injectable Double Crosslinked Hydrogel‐Polypropylene Composite Mesh for Repairing Full‐Thickness Abdominal Wall Defects
Authors: Yixin Zhao, Xiaopei Li, Ni Sun, Yan Mao, Teng Ma, Xiangping Liu, Tao Cheng, Xiangyu Shao, Haifeng Zhang, Xianggang Huang, Junsheng Li, Ningping Huang, Haibo Wang
Journal: Advanced Healthcare Materials (2024)

Abstract Abdominal wall defects are common clinical diseases, and mesh repair is the standard treatment method. The most commonly used polypropylene (PP) mesh in clinical practice has the advantages of good mechanical properties, stable performance, and effective tissue integration effect. However, direct contact between abdominal viscera and PP mesh can lead to severe abdominal adhesions. To prevent this, the development of a hydrogel‐PP composite mesh with anti‐adhesive properties may be an effective measure. Herein, biofunctional hydrogel loaded with rosmarinic acid is developed by modifying chitosan and Pluronic F127, which possesses suitable physical and chemical properties and commendable in vitro biocompatibility. In the repair of full‐thickness abdominal wall defects in rats, hydrogels are injected onto the surface of PP mesh and applied to intraperitoneal repair. The results indicate that the use of hydrogel‐PP composite mesh can alleviate abdominal adhesions resulting from traditional PP mesh implantation by decreasing local inflammatory response, reducing oxidative stress, and regulating the fibrinolytic system. Combined with the tissue integration ability of PP mesh, hydrogel‐PP composite mesh has great potential for repairing full‐thickness abdominal wall defects.
Trastuzumab and Pertuzumab in Patients with Non-Breast/Gastroesophageal <i>HER2</i>-Amplified Tumors: Results from the NCI–MATCH ECOG–ACRIN Trial (EAY131) Subprotocol J
Authors: Roisin M. Connolly, Victoria Wang, David M. Hyman, Petros Grivas, Edith P. Mitchell, John J. Wright, Elad Sharon, Robert J. Gray, Lisa M. McShane, Larry V. Rubinstein, David R. Patton, P. Mickey Williams, Stanley R. Hamilton, Jue Wang, Kari B. Wisinski, James V. Tricoli, Barbara A. Conley, Lyndsay N. Harris, Carlos L. Arteaga, Peter J. O'Dwyer, Alice P. Chen, Keith T. Flaherty
Journal: Clinical Cancer Research (2024)

Abstract Purpose: NCI–MATCH assigned patients with advanced cancer and progression on prior treatment, based on genomic alterations in pretreatment tumor tissue. Arm J (EAY131-J) evaluated the combination of trastuzumab/pertuzumab (HP) across HER2-amplified tumors. Patients and Methods: Eligible patients had high levels of HER2 amplification [copy number (CN) ≥7] detected by central next-generation sequencing (NGS) or through NCI-designated laboratories. Patients with breast/gastroesophageal adenocarcinoma and those who received prior HER2-directed therapy were excluded. Enrollment of patients with colorectal cancer was capped at 4 based on emerging data. Patients received HP IV Q3 weeks until progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS) and overall survival (OS). Results: Thirty-five patients were enrolled, with 25 included in the primary efficacy analysis (CN ≥7 confirmed by a central lab, median CN = 28). Median age was 66 (range, 31–80), and half of all patients had ≥3 prior therapies (range, 1–11). The confirmed ORR was 12% [3/25 partial responses (colorectal, cholangiocarcinoma, urothelial cancers), 90% confidence interval (CI) 3.4%–28.2%]. There was one additional partial response (urothelial cancer) in a patient with an unconfirmed ERBB2 copy number. Median PFS was 3.3 months (90% CI 2.0–4.1), and median OS 9.4 months (90% CI 5.0–18.9). Treatment-emergent adverse events were consistent with prior studies. There was no association between HER2 CN and response. Conclusions: HP was active in a selection of HER2-amplified tumors (non-breast/gastroesophageal) but did not meet the predefined efficacy benchmark. Additional strategies targeting HER2 and potential resistance pathways are warranted, especially in rare tumors.
Abstract A051: Treatment outcome of leptomeningeal metastasis from breast cancer
Authors: Suzy Kim, Choong-won Lee
Journal: Cancer Research (2024)

Abstract Purpose: Leptomeningeal metastasis (LM) is well-known for its dismal prognosis. Despite various treatment approaches, there has been minimal improvement in survival, and the optimal treatment for leptomeningeal metastasis remains uncertain. Our study aimed to report treatment outcomes using different modalities for LM and to identify prognostic factors. Materials and Methods: We analyzed 111 breast cancer patients with LM, who were treated at Seoul National University and Seoul Metropolitan Government Seoul National University Boramae Medical Center between January 2010 and December 2022. The median follow-up period was 4.4 months (range, 0.2 – 125.4 months). Results: The median age was 48 years, with the majority having a Karnofsky performance status below 60 (n = 100, 90.1%). Among the 111 patients, intrathecal chemotherapy was the most commonly used treatment modality (n = 89, 80.2%), followed by radiotherapy (n = 74, 66.7%), and systemic chemotherapy (n = 56, 50.5%). The median freedom from progression was 3.4 months. In multivariate analysis, patients who underwent more than 2 treatment modalities experienced significantly longer progression-free interval (1.8 months vs. 7.4 months, HR = 0.20, p = 0.038). Additionally, patients who underwent excision of the primary breast tumor displayed a tendency for longer progression-free interval (3.1 months vs. 3.4 months, HR = 0.33, p = 0.084). Patients with systemic inflammation index greater than 500 × 103/mm3 at the time of the diagnosis of LM exhibited shorter progression-free interval (3.5 months vs. 2.9 months, HR = 2.88, p = 0.056). There was no difference of progression-free interval according to treatment modalities. Conclusions: The freedom from progression of LM originating from breast cancer was found to be poor, exhibiting less than 4 months. A multimodal approach upon LM and high systemic inflammation index at the time of the diagnosis of LM demonstrated significant difference in prognosis. Further research is warranted to elucidate the clinical implications and develop optimized treatment strategie Citation Format: Suzy Kim, Choong-won Lee. Treatment outcome of leptomeningeal metastasis from breast cancer [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A051.
Abstract A015: Predicting efficacious drugs and drug-biomarker relationships for targeted glioblastoma treatment
Authors: Danielle Maeser, Robert Gruener, Robert Galvin, Stephanie Huang, Tomo Koga, Florina Grigore
Journal: Cancer Research (2024)

Abstract Glioblastoma multiforme (GBM) is the deadliest, most heterogeneous, and common brain cancer in adults. Despite major advancements in neurosurgery as well as chemotherapy and radiotherapy techniques, overall prognosis has changed little over the decades. Not only is there an urgent need to identify efficacious therapeutics but there is also a great need to pair these therapeutics with biomarkers that can help tailor treatment to the right patient populations given the heterogeneous nature of the disease. Here, we implement several machine learning and statistical based pipelines for drug and biomarker discovery, leveraging previous work building patient drug response models using high-throughput cell line drug screening data as well as Bayesian network structure learning. Through these discovery pipelines, we identified multiple agents of interest for GBM, including MEK inhibitors (MEKis). MEKis were consistently predicted to be effective against GBM in multiple cross platform (microarray and RNA-sequencing) patient and patient derived xenograft (PDX) datasets. Additionally, they were experimentally shown to be more efficacious in tumor samples than standard of care agents (Temozolomide and Carmustine). We also predicted PHGDH gene expression levels to be causally associated with MEKi efficacy, which increased tumor sensitivity to a MEKi (Trametinib) during experimental testing in GBM cell lines with knockdown. These findings support our drug and biomarker discovery pipelines as an effective strategy to unite multiple cross platform and cross species datasets to help achieve GBM precision medicine. They also demonstrate that patient PHGDH levels can help inform Trametinib response in the fight against GBM. Citation Format: Danielle Maeser, Robert Gruener, Robert Galvin, Stephanie Huang, Tomo Koga, Florina Grigore. Predicting efficacious drugs and drug-biomarker relationships for targeted glioblastoma treatment [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A015.
Abstract A035: Radiation-induced senescence as a driver of glioblastoma recurrence
Authors: Ben R. Jordan, Nozomi Tomimatsu, Luis Macedo Di Cristofaro, Suman Kanji, Bipasha Mukherjee, Sandeep Burma
Journal: Cancer Research (2024)

Abstract Glioblastomas (GBM) are treated with high doses of ionizing radiation (IR), yet these tumors inevitably recur, and the recurrent tumors are highly therapy resistant. An understanding of mechanisms driving GBM recurrence is critical for improving therapy. During GBM therapy, both the tumor and normal brain tissue surrounding the tumor are treated with up to 60 Gy of IR. IR is a potent inducer of senescence, and senescent stromal cells can promote the growth of neighboring tumor cells by secreting matrix metalloproteinases, chemokines, cytokines, and growth factors that create a senescence-associated secretory phenotype (SASP). We have shown previously that IR-induced senescence of astrocytes in the brain leads to the secretion of SASP factors that promote the growth and invasiveness of tumor cells in mouse models of GBM (Fletcher-Sananikone, et al, Cancer Research, 2021). Following up on this study, we irradiated a panel of GBM cell lines and found that a significant fraction of these senesced rapidly in a p21-dependent manner. Senescent glioma cells upregulated SASP genes in a NF-kB-dependent manner, prominently, the interleukin IL6, which is an activator of the JAK-STAT pathway. Conditioned media from senescent GBM cells activated the JAK-STAT pathway in non-senescent GBM cells as well as promoted tumor cell proliferation and radioresistance. Interestingly, conditioned media from senescent GBM cells could also activate the NF-kB pathway and induce SASP in non-senescent cells. These results indicate that senescent GBM cells can activate pro-tumorigenic pathways in their non-senescent counterparts and SASP can spread from senescent to non-senescent cells. Bioinformatic analyses of the transcriptomic profiles of irradiated GBM cells and publicly available data from the TCGA database revealed that the inhibitor of apoptosis protein cIAP2 is a critical survival factor for senescent glioma cells. We find that targeting cIAP2 using Smac mimetics triggers apoptosis of senescent GBM cells with minimal toxicity towards normal brain cells, like astrocytes. Upregulation of cIAP2 in irradiated tumor cells was also observed in PDX models of GBM. Using these PDX models, we are currently validating novel senolytic-based therapeutic approaches to mitigate tumor recurrence after radiotherapy. In sum, our findings illustrate how senescence of both stromal and tumor cells promote GBM recurrence via different mechanisms and underscore the potential utility of adjuvant senolytic therapy for blunting GBM recurrence after radiotherapy. Citation Format: Ben R. Jordan, Nozomi Tomimatsu, Luis Macedo Di Cristofaro, Suman Kanji, Bipasha Mukherjee, Sandeep Burma. Radiation-induced senescence as a driver of glioblastoma recurrence [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A035.
Abstract A006: Reckless mitotic entry as a novel chemosensitization approach for alkylating agents
Authors: Fengchao Lang, James Cornwell, Karambir Kaur, Omar Elmogazy, Wei Zhang, Meili Zhang, Hua Song, Zhonghe Sun, Xiaolin Wu, Mirit I. Aladjem, Michael Aregger, Steven Cappell, Chunzhang Yang
Journal: Cancer Research (2024)

Abstract The cell cycle is tightly regulated by checkpoints, playing a vital role in controlling its progression and timing. Cancer cells exploit the G2/M checkpoint, which serves as a resistance mechanism against genotoxic anti-cancer treatments, allowing for DNA repair prior to cell division. Therefore, manipulating cell cycle timing has emerged as a potential strategy to augment the effectiveness of DNA damage-based therapies such as alkylating agents and radiation. In this study, we conducted a forward genome wide CRISPR/Cas9 screening with repeated exposure to the alkylating agent temozolomide (TMZ) to investigate the mechanisms underlying tumor cell survival under genotoxic stress. Our findings revealed that canonical DNA repair pathways, including ATM/Fanconi and mismatch repair, determine cell fate under genotoxic stress. Notably, we identified the critical role of the membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase, known as Myt1 (encoded by PKMYT1), in ensuring cell survival. Depletion of PKMYT1 led to overwhelming TMZ-induced cytotoxicity in cancer cells. Isobologram analysis demonstrated potent drug synergy between TMZ and other clinically used alkylating agents, such as carmustine, busulfan, and dacarbazine, when combined with a novel Myt1 kinase inhibitor, RP-6306. Mechanistically, inhibiting Myt1 forced G2/M-arrested cells into an unscheduled transition to the mitotic phase without complete resolution of DNA damage, as indicated by a substantial increase in γH2AX-positive cells in mitosis. Moreover, RP-6306 dramatically altered cell cycle timing, reducing the threshold time for mitotic entry. This forced entry into mitosis, along with persistent DNA damage, resulted in severe mitotic abnormalities, including unaligned and partially condensed chromosomes, lagging chromosomes, chromosome bridges, and multipolar spindles. Ultimately, these aberrations led to mitotic exit with substantial apoptosis. Importantly, preclinical animal studies demonstrated that the combination regimen involving TMZ and RP-6306 prolonged the overall survival of glioma-bearing mice. Collectively, our findings highlight the potential of targeting cell cycle timing through Myt1 inhibition as a novel strategy to enhance the efficacy of current standard cancer therapies, potentially leading to improved disease outcomes. Citation Format: Fengchao Lang, James Cornwell, Karambir Kaur, Omar Elmogazy, Wei Zhang, Meili Zhang, Hua Song, Zhonghe Sun, Xiaolin Wu, Mirit I. Aladjem, Michael Aregger, Steven Cappell, Chunzhang Yang. Reckless mitotic entry as a novel chemosensitization approach for alkylating agents [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A006.
Abstract A020: Neural stem cells expressing PTEN-L suppress glioblastoma invasion <i>in vivo</i>
Authors: Ian A. Lorimer, Margarita Lui, Sylvie J. Lavictoire, Josee Coulombe
Journal: Cancer Research (2024)

Abstract Purpose: The purpose of this study is to evaluate the therapeutic potential of neural stem cells expressing PTEN-L (a variant of the tumor suppressor PTEN that can transfer between cells) in preclinical glioblastoma models. Experimental procedures: Human neural stem cells derived by direct reprogramming of peripheral blood erythroblasts were used. Using lentiviral transduction, these were engineered for doxycycline-inducible expression of a modified version of PTEN-L with optimized expression and enhanced cell-to-cell transfer properties. Expression of PTEN-L was assayed by Western blot analysis. These engineered neural stem cells were evaluated in an orthotopic mouse xenograft model in which human glioblastoma cells show extensive invasion into the uninjected hemisphere. Neural stem cells and glioblastoma cells were co-injected and mice were then randomized to chow with or without doxycycline. Mice were evaluated for overall survival and for invasion of glioblastoma cells into the uninjected hemisphere. Results: When injected intracerebrally into immunocompromised mice, peripheral blood-derived neural stem cells persisted for over four months and showed an ability to spontaneously migrate to sites distant from the injection site. When co-injected with human glioblastoma cells from patients, the neural stem cells co-migrated with glioblastoma cells along the corpus callosum and to distant sites. Peripheral blood-derived neural stem cells transduced with lentiviral vectors for doxycycline-inducible PTEN-L efficiently secreted PTEN-L. In the orthotopic mouse xenograft glioblastoma model, expression of PTEN-L by neural stem cells did not significantly improve survival in mice (log rank P = 0.5) but did significantly repress glioblastoma cell invasion into the uninjected hemisphere (two-tailed t-test P = 0.02). Conclusions. Peripheral blood-derived neural stem cells show good persistence and migrate with human glioblastoma cells in vivo. They can be engineered to efficiently secret functional PTEN-L. Peripheral blood-derived neural stem cells expressing PTEN-L do not increase survival in the one patient model tested but do repress invasion. This initial evidence for bioactivity supports further studies evaluating the ability of neural stem cells expressing PTEN-L to sensitize glioblastoma to therapeutics for which PTEN loss has been implicated in resistance. Citation Format: Ian A. Lorimer, Margarita Lui, Sylvie J. Lavictoire, Josee Coulombe. Neural stem cells expressing PTEN-L suppress glioblastoma invasion in vivo [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A020.
Abstract A001: Silencing of EYA4 regulates stemness in H3K27M-mutant diffuse midline glioma
Authors: Ivana Barravecchia, Monika Sharma, Brian Magnuson, Sarah F. Ferris, April Apfelbaum, Carl Koschmann, Costas A. Lyssiotis, Mats Ljungman, Stefanie Galban
Journal: Cancer Research (2024)

Abstract Therapeutic resistance remains a major obstacle to preventing progression of H3K27M-altered Diffuse Midline Glioma (DMG). Resistance is driven in part by ALDH-positive cancer stem cells (CSC), with high ALDH1A3 expression observed in H3K27M-mutant DMG biopsies. We hypothesized that ALDH-mediated stemness and resistance may in part be driven by the oncohistone itself. Upon deletion of H3K27M, ALDH1A3 expression decreased dramatically and was accompanied by a gain in astrocytic marker expression and a loss of neurosphere forming potential, indicative of changes in differentiation. Here we show that the oncohistone regulates histone acetylation through ALDH1A3 in a Wnt-dependent manner and that loss of H3K27M expression results in re-sensitization of DMGs to radiotherapy. The observed elevated Wnt signaling in H3K27M-altered DMG likely stems from a dramatic suppression of mRNA and protein expression of the Wnt inhibitor EYA4 driven by the oncohistone. Thus, our findings identify EYA4 as a bona fide tumor suppressor in DMG that upon suppression, results in aberrant Wnt signaling to orchestrate stemness and differentiation. Future studies will therefore explore whether overexpression of EYA4 in DMG can impede growth and invasion. In summary, we have gained mechanistic insight into H3K27M-mediated regulation of cancer stemness and differentiation, which provides rationale for exploring new therapeutic targets for DMG. Citation Format: Ivana Barravecchia, Monika Sharma, Brian Magnuson, Sarah F. Ferris, April Apfelbaum, Carl Koschmann, Costas A. Lyssiotis, Mats Ljungman, Stefanie Galban. Silencing of EYA4 regulates stemness in H3K27M-mutant diffuse midline glioma [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A001.
Abstract A033: Murine CNS and bone marrow distribution of the aurora A kinase inhibitor alisertib: Pharmacokinetics and exposure at the sites of efficacy and toxicity
Authors: Juhee Oh, Erica A. Power, Wenjuan Zhang, David J. Daniels, William F. Elmquist
Journal: Cancer Research (2024)

Abstract Important challenges in developing drugs that target central nervous system (CNS) tumors include overcoming barriers for CNS delivery and reducing systemic side effects. Alisertib, an aurora A kinase inhibitor, has been examined for treatment of several CNS tumors in preclinical and clinical studies. In this study, we investigated the distribution of alisertib into the CNS, the site of efficacy for brain tumors, and into the bone marrow, the site of dose-limiting toxicity leading to myelosuppression. Mechanisms influencing site-specific distribution, such as active transport mediated by the efflux proteins, p-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), were examined. Alisertib exposure to the brain in wild-type mice was less than 1% of that in the plasma and was evenly distributed throughout various brain regions and the spinal cord. Studies using transporter knockout mice and pharmacological inhibition show that alisertib CNS distribution is influenced by P-gp, but not Bcrp. Conversely, upon systemic administration, alisertib distribution to the bone marrow occurred rapidly, was not significantly limited by efflux transporters, and reached higher concentrations than in the CNS. This study demonstrates that, given an equivalent distributional driving force exposure in plasma, the exposure of alisertib in the brain is significantly less than that in the bone marrow, suggesting that targeted delivery may be necessary to guarantee therapeutic efficacy with minimal risk for adverse events. Therefore, these data suggest that, to improve the therapeutic index when using alisertib for brain tumors, a localized regional delivery, such as convection-enhanced delivery, may be warranted. Citation Format: Juhee Oh, Erica A. Power, Wenjuan Zhang, David J. Daniels, William F. Elmquist. Murine CNS and bone marrow distribution of the aurora A kinase inhibitor alisertib: Pharmacokinetics and exposure at the sites of efficacy and toxicity [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A033.