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31 results on '"Karve, Aniruddha"'

3. GABA(A) Receptor Activation Drives GABARAP–Nix Mediated Autophagy to Radiation-Sensitize Primary and Brain-Metastatic Lung Adenocarcinoma Tumors.

Author

Bhattacharya, Debanjan, Barrile, Riccardo, Toukam, Donatien Kamdem, Gawali, Vaibhavkumar S., Kallay, Laura, Ahmed, Taukir, Brown, Hawley, Rezvanian, Sepideh, Karve, Aniruddha, Desai, Pankaj B., Medvedovic, Mario, Wang, Kyle, Ionascu, Dan, Harun, Nusrat, Vallabhapurapu, Subrahmanya, Wang, Chenran, Qi, Xiaoyang, Baschnagel, Andrew M., Kritzer, Joshua A., and Cook, James M.

Subjects
PROTEINS, ADENOCARCINOMA, IN vitro studies, AUTOPHAGY, MITOCHONDRIA, DATA analysis, RESEARCH funding, POLYMERASE chain reaction, IN vivo studies, FLUORESCENT antibody technique, XENOGRAFTS, DESCRIPTIVE statistics, RADIATION-sensitizing agents, METASTASIS, CYTOTOXINS, CELL lines, IMMUNOHISTOCHEMISTRY, KAPLAN-Meier estimator, MOLECULAR structure, ONE-way analysis of variance, STATISTICS, LUNG cancer, STAINS & staining (Microscopy), CELL survival, DATA analysis software, CELL receptors, GABA, BRAIN tumors, ELECTROPHYSIOLOGY, IMMUNOBLOTTING, CHEMICAL inhibitors
Abstract

Simple Summary: Non-small cell lung cancer (NSCLC) accounts for 80–85% of primary lung cancers. Radiation therapy is widely used to treat both primary NSCLC and lung cancer that has spread to the brain. However, radiotherapy responses are not durable and toxicity limits therapy. Therefore, there is an urgent need for new agents that can enhance the effectiveness of radiation therapy in lung cancer and reduce its toxicity. We find that AM-101, a benzodiazepine analog, enhances the effects of radiation and significantly improves the survival of mice with lung cancer brain-metastatic tumors. Additionally, AM-101 makes radiation treatment work better and slows down the growth of NSCLC subcutaneous xenograft tumors in mice. AM-101 activates the GABA(A) receptor in lung cancer cells, triggering selective autophagy by causing GABARAP to form multimers and stabilizing the mitochondrial receptor Nix. GABA(A) receptor activation may improve tumor control and allow for lower radiation doses, reducing toxicity. In non-small cell lung cancer (NSCLC) treatment, radiotherapy responses are not durable and toxicity limits therapy. We find that AM-101, a synthetic benzodiazepine activator of GABA(A) receptor, impairs the viability and clonogenicity of both primary and brain-metastatic NSCLC cells. Employing a human-relevant ex vivo 'chip', AM-101 is as efficacious as docetaxel, a chemotherapeutic used with radiotherapy for advanced-stage NSCLC. In vivo, AM-101 potentiates radiation, including conferring a significant survival benefit to mice bearing NSCLC intracranial tumors generated using a patient-derived metastatic line. GABA(A) receptor activation stimulates a selective-autophagic response via the multimerization of GABA(A) receptor-associated protein, GABARAP, the stabilization of mitochondrial receptor Nix, and the utilization of ubiquitin-binding protein p62. A high-affinity peptide disrupting Nix binding to GABARAP inhibits AM-101 cytotoxicity. This supports a model of GABA(A) receptor activation driving a GABARAP–Nix multimerization axis that triggers autophagy. In patients receiving radiotherapy, GABA(A) receptor activation may improve tumor control while allowing radiation dose de-intensification to reduce toxicity. [ABSTRACT FROM AUTHOR]

Published
2024
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4. Supplemental Table 7 from A Phase 0/I Pharmacokinetic and Pharmacodynamics and Safety and Tolerability Study of Letrozole in Combination with Standard Therapy in Recurrent High-Grade Gliomas

Author

Desai, Pankaj B., primary, Karve, Aniruddha S., primary, Zawit, Misam, primary, Arora, Priyanka, primary, Dave, Nimita, primary, Awosika, Joy, primary, Li, Ningjing, primary, Fuhrman, Bethany, primary, Medvedovic, Mario, primary, Sallans, Larry, primary, Kendler, Ady, primary, DasGupta, Biplab, primary, Plas, David, primary, Curry, Richard, primary, Zuccarello, Mario, primary, Chaudhary, Rekha, primary, Sengupta, Soma, primary, and Wise-Draper, Trisha M., primary

Published
2024
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5. Supplemental Table 2 from A Phase 0/I Pharmacokinetic and Pharmacodynamics and Safety and Tolerability Study of Letrozole in Combination with Standard Therapy in Recurrent High-Grade Gliomas

Author

Desai, Pankaj B., primary, Karve, Aniruddha S., primary, Zawit, Misam, primary, Arora, Priyanka, primary, Dave, Nimita, primary, Awosika, Joy, primary, Li, Ningjing, primary, Fuhrman, Bethany, primary, Medvedovic, Mario, primary, Sallans, Larry, primary, Kendler, Ady, primary, DasGupta, Biplab, primary, Plas, David, primary, Curry, Richard, primary, Zuccarello, Mario, primary, Chaudhary, Rekha, primary, Sengupta, Soma, primary, and Wise-Draper, Trisha M., primary

Published
2024
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6. Supplemental Figure 2 from A Phase 0/I Pharmacokinetic and Pharmacodynamics and Safety and Tolerability Study of Letrozole in Combination with Standard Therapy in Recurrent High-Grade Gliomas

Author

Desai, Pankaj B., primary, Karve, Aniruddha S., primary, Zawit, Misam, primary, Arora, Priyanka, primary, Dave, Nimita, primary, Awosika, Joy, primary, Li, Ningjing, primary, Fuhrman, Bethany, primary, Medvedovic, Mario, primary, Sallans, Larry, primary, Kendler, Ady, primary, DasGupta, Biplab, primary, Plas, David, primary, Curry, Richard, primary, Zuccarello, Mario, primary, Chaudhary, Rekha, primary, Sengupta, Soma, primary, and Wise-Draper, Trisha M., primary

Published
2024
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7. Supplemental Figure 1 from A Phase 0/I Pharmacokinetic and Pharmacodynamics and Safety and Tolerability Study of Letrozole in Combination with Standard Therapy in Recurrent High-Grade Gliomas

Author

Desai, Pankaj B., primary, Karve, Aniruddha S., primary, Zawit, Misam, primary, Arora, Priyanka, primary, Dave, Nimita, primary, Awosika, Joy, primary, Li, Ningjing, primary, Fuhrman, Bethany, primary, Medvedovic, Mario, primary, Sallans, Larry, primary, Kendler, Ady, primary, DasGupta, Biplab, primary, Plas, David, primary, Curry, Richard, primary, Zuccarello, Mario, primary, Chaudhary, Rekha, primary, Sengupta, Soma, primary, and Wise-Draper, Trisha M., primary

Published
2024
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8. Supplemental Table 1 from A Phase 0/I Pharmacokinetic and Pharmacodynamics and Safety and Tolerability Study of Letrozole in Combination with Standard Therapy in Recurrent High-Grade Gliomas

Author

Desai, Pankaj B., primary, Karve, Aniruddha S., primary, Zawit, Misam, primary, Arora, Priyanka, primary, Dave, Nimita, primary, Awosika, Joy, primary, Li, Ningjing, primary, Fuhrman, Bethany, primary, Medvedovic, Mario, primary, Sallans, Larry, primary, Kendler, Ady, primary, DasGupta, Biplab, primary, Plas, David, primary, Curry, Richard, primary, Zuccarello, Mario, primary, Chaudhary, Rekha, primary, Sengupta, Soma, primary, and Wise-Draper, Trisha M., primary

Published
2024
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9. Supplemental Table 4 from A Phase 0/I Pharmacokinetic and Pharmacodynamics and Safety and Tolerability Study of Letrozole in Combination with Standard Therapy in Recurrent High-Grade Gliomas

Author

Desai, Pankaj B., primary, Karve, Aniruddha S., primary, Zawit, Misam, primary, Arora, Priyanka, primary, Dave, Nimita, primary, Awosika, Joy, primary, Li, Ningjing, primary, Fuhrman, Bethany, primary, Medvedovic, Mario, primary, Sallans, Larry, primary, Kendler, Ady, primary, DasGupta, Biplab, primary, Plas, David, primary, Curry, Richard, primary, Zuccarello, Mario, primary, Chaudhary, Rekha, primary, Sengupta, Soma, primary, and Wise-Draper, Trisha M., primary

Published
2024
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10. Supplemental Table 3 from A Phase 0/I Pharmacokinetic and Pharmacodynamics and Safety and Tolerability Study of Letrozole in Combination with Standard Therapy in Recurrent High-Grade Gliomas

Author

Desai, Pankaj B., primary, Karve, Aniruddha S., primary, Zawit, Misam, primary, Arora, Priyanka, primary, Dave, Nimita, primary, Awosika, Joy, primary, Li, Ningjing, primary, Fuhrman, Bethany, primary, Medvedovic, Mario, primary, Sallans, Larry, primary, Kendler, Ady, primary, DasGupta, Biplab, primary, Plas, David, primary, Curry, Richard, primary, Zuccarello, Mario, primary, Chaudhary, Rekha, primary, Sengupta, Soma, primary, and Wise-Draper, Trisha M., primary

Published
2024
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11. Supplemental Table 5 from A Phase 0/I Pharmacokinetic and Pharmacodynamics and Safety and Tolerability Study of Letrozole in Combination with Standard Therapy in Recurrent High-Grade Gliomas

Author

Desai, Pankaj B., primary, Karve, Aniruddha S., primary, Zawit, Misam, primary, Arora, Priyanka, primary, Dave, Nimita, primary, Awosika, Joy, primary, Li, Ningjing, primary, Fuhrman, Bethany, primary, Medvedovic, Mario, primary, Sallans, Larry, primary, Kendler, Ady, primary, DasGupta, Biplab, primary, Plas, David, primary, Curry, Richard, primary, Zuccarello, Mario, primary, Chaudhary, Rekha, primary, Sengupta, Soma, primary, and Wise-Draper, Trisha M., primary

Published
2024
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12. Data from A Phase 0/I Pharmacokinetic and Pharmacodynamics and Safety and Tolerability Study of Letrozole in Combination with Standard Therapy in Recurrent High-Grade Gliomas

Author

Desai, Pankaj B., primary, Karve, Aniruddha S., primary, Zawit, Misam, primary, Arora, Priyanka, primary, Dave, Nimita, primary, Awosika, Joy, primary, Li, Ningjing, primary, Fuhrman, Bethany, primary, Medvedovic, Mario, primary, Sallans, Larry, primary, Kendler, Ady, primary, DasGupta, Biplab, primary, Plas, David, primary, Curry, Richard, primary, Zuccarello, Mario, primary, Chaudhary, Rekha, primary, Sengupta, Soma, primary, and Wise-Draper, Trisha M., primary

Published
2024
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13. Supplemental Table 6 from A Phase 0/I Pharmacokinetic and Pharmacodynamics and Safety and Tolerability Study of Letrozole in Combination with Standard Therapy in Recurrent High-Grade Gliomas

Author

Desai, Pankaj B., primary, Karve, Aniruddha S., primary, Zawit, Misam, primary, Arora, Priyanka, primary, Dave, Nimita, primary, Awosika, Joy, primary, Li, Ningjing, primary, Fuhrman, Bethany, primary, Medvedovic, Mario, primary, Sallans, Larry, primary, Kendler, Ady, primary, DasGupta, Biplab, primary, Plas, David, primary, Curry, Richard, primary, Zuccarello, Mario, primary, Chaudhary, Rekha, primary, Sengupta, Soma, primary, and Wise-Draper, Trisha M., primary

Published
2024
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14. A Phase 0/1 Pharmacokinetic and Pharmacodynamics and Safety and Tolerability Study of Letrozole in Combination with Standard Therapy in Recurrent High-Grade Gliomas

Author

Desai, Pankaj B., primary, Karve, Aniruddha, additional, Zawit, Misam, additional, Arora, Priyanka, additional, Dave, Nimita, additional, Awosika, Joy, additional, Li, Ningjing, additional, Fuhrman, Bethany, additional, Medvedovic, Mario, additional, Sallans, Larry, additional, Kendler, Ady, additional, DasGupta, Biplab, additional, Plas, David, additional, Curry, Richard, additional, Zuccarello, Mario, additional, Chaudhary, Rekha, additional, Sengupta, Soma, additional, and Wise-Draper, Trisha M., additional

Published
2024
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15. A Review of Approaches to Potentiate the Activity of Temozolomide against Glioblastoma to Overcome Resistance

Author

Karve, Aniruddha S., primary, Desai, Janki M., additional, Gadgil, Sidharth N., additional, Dave, Nimita, additional, Wise-Draper, Trisha M., additional, Gudelsky, Gary A., additional, Phoenix, Timothy N., additional, DasGupta, Biplab, additional, Yogendran, Lalanthica, additional, Sengupta, Soma, additional, Plas, David R., additional, and Desai, Pankaj B., additional

Published
2024
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17. Pharmacokinetics of Levetiracetam Seizure Prophylaxis in Severe Traumatic Brain Injury

Author

Harlan, Sarah Schuman, primary, Philpott, Carolyn D., additional, Keegan, Shaun P., additional, Droege, Molly E., additional, Karve, Aniruddha S., additional, Foreman, Brandon, additional, Wakefield, Devin, additional, Mueller, Eric W, additional, Sangha, Kiranpal, additional, Ngwenya, Laura B., additional, Courter, Joshua D., additional, Desai, Pankaj, additional, and Droege, Christopher, additional

Published
2023
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18. 1286: IMPACT OF AUGMENTED RENAL CLEARANCE ON VANCOMYCIN IN CRITICALLY ILL TRAUMA PATIENTS

Author

Rice, Timothy, primary, Droege, Molly, additional, Philpott, Carolyn, additional, Courter, Joshua, additional, Desai, Pankaj, additional, Harger, Nicole, additional, Ernst, Neil, additional, Foertsch, Madeline, additional, Healy, Daniel, additional, Karve, Aniruddha, additional, Liao, Siyun, additional, Mueller, Eric, additional, Winter, Jessica, additional, Goodman, Michael, additional, and Droege, Chris, additional

Published
2022
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19. RBIO-02. ACTIVATION OF GABAA RECEPTORS WITH A NON-TOXIC, BRAIN PENETRANT SMALL MOLECULE SENSITIZES LUNG ADENOCARCINOMA PRIMARY AND BRAIN METASTATIC TUMOR CELLS TO RADIATION VIA AUTOPHAGY INDUCTION

Author

Bhattacharya, Debanjan, primary, Barille, Riccardo, additional, Toukam, Donatien Kamdem, additional, Gawali, Vaibhavkumar, additional, Kallay, Laura, additional, Ahmed, Taukir, additional, Cook, James, additional, Karve, Aniruddha, additional, Desai, Pankaj, additional, Medvedovic, Mario, additional, Krummel, Daniel Pomeranz, additional, and Sengupta, Soma, additional

Published
2022
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21. EXTH-99. SYSTEMIC AND BRAIN PHARMACOKINETICS OF A GABAA RECEPTOR AGONIST, AMLAL-101, AS AN INVESTIGATIONAL THERAPEUTIC FOR THE TREATMENT OF PRIMARY AND METASTATIC BRAIN CANCERS

Author

Karve, Aniruddha, primary, Ahmed, Taukir, additional, Desai, Janki, additional, Bhattacharya, Debanjan, additional, Toukam, Donatien Kamdem, additional, Gadgil, Sidharth, additional, Pemberton, Merissa, additional, Plas, David, additional, Gudelsky, Gary, additional, Sallans, Larry, additional, Cook, James, additional, Desai, Pankaj, additional, Krummel, Daniel Pomeranz, additional, and Sengupta, Soma, additional

Published
2022
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22. RBIO-01. ACTIVATING AN ION CHANNEL PROMOTES RADIATION-SENSITIZING IMMUNE-DRIVEN ANTI-TUMOR ACTIVITY

Author

Toukam, Donatien Kamdem, primary, Bhattacharya, Debanjan, additional, Gawali, Vaibhavkumar, additional, Kallay, Laura, additional, Karve, Aniruddha, additional, Desai, Pankaj, additional, Cook, James, additional, Ahmed, Taukir, additional, Ionascu, Trajan Dan, additional, Tridandapani, Susheela, additional, Krummel, Daniel Pomeranz, additional, and Sengupta, Soma, additional

Published
2022
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24. A First-In-Class, Humanized Antibody Targeting Alternatively Spliced Tissue Factor: Preclinical Evaluation in an Orthotopic Model of Pancreatic Ductal Adenocarcinoma

Author

Lewis, Clayton S., primary, Karve, Aniruddha, additional, Matiash, Kateryna, additional, Stone, Timothy, additional, Li, Jingxing, additional, Wang, Jordon K., additional, Versteeg, Henri H., additional, Aronow, Bruce J., additional, Ahmad, Syed A., additional, Desai, Pankaj B., additional, and Bogdanov, Vladimir Y., additional

Published
2021
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25. Abstract 908: Preclinical in vivo characterization of a first-in-class humanized antibody targeting alternatively spliced tissue factor

Author

Lewis, Clayton S., primary, Karve, Aniruddha, additional, Matiash, Kateryna, additional, Stone, Timothy, additional, Li, Jingxing, additional, Wang, Jordan, additional, Versteeg, Henri, additional, Aronow, Bruce, additional, Ahmad, Syed, additional, Desai, Pankaj, additional, and Bogdanov, Vladimir, additional

Published
2021
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26. Phosphoinositide 3-Kinase (PI3K) Reactive Oxygen Species (ROS)-Activated Prodrug in Combination with Anthracycline Impairs PI3K Signaling, Increases DNA Damage Response and Reduces Breast Cancer Cell Growth

Author

Mishra, Rosalin, primary, Yuan, Long, additional, Patel, Hima, additional, Karve, Aniruddha S., additional, Zhu, Haizhou, additional, White, Aaron, additional, Alanazi, Samar, additional, Desai, Pankaj, additional, Merino, Edward J., additional, and Garrett, Joan T., additional

Published
2021
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27. Reuse of Molecules for Glioblastoma Therapy

Author

Koehler, Abigail, primary, Karve, Aniruddha, additional, Desai, Pankaj, additional, Arbiser, Jack, additional, Plas, David R., additional, Qi, Xiaoyang, additional, Read, Renee D., additional, Sasaki, Atsuo T., additional, Gawali, Vaibhavkumar S., additional, Toukam, Donatien K., additional, Bhattacharya, Debanjan, additional, Kallay, Laura, additional, Pomeranz Krummel, Daniel A., additional, and Sengupta, Soma, additional

Published
2021
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30. Translational Research to Facilitate Development of Novel Therapeutics for the Treatment of Glioblastoma

Author

Karve, Aniruddha

Subjects
Pharmaceuticals, Glioblastoma, Blood-brain barrier, Translational, Aromatase, Letrozole, AML-101
Abstract

Glioblastoma (GBM) is one of the most aggressive malignant brain tumors with a dismal prognosis. Current treatment modalities for GBM include maximally safe surgical resection, followed by radiation therapy and concomitant administration of temozolomide (TMZ), the only chemotherapeutic agent approved for this purpose. However, this multimodal approach of treatment fails to eradicate the disease and tumors develop resistance to TMZ. Thus, there is an urgent unmet need to develop novel therapeutics for GBM to act as monotherapy and/or as a combination agent with TMZ. In this study we carried out translational studies on lead compounds that target 2 novel receptors abundantly expressed in GBM; ?-aminobutyric acid receptor-a (a5-GABAA) and aromatase, an estrogen synthase enzyme. The first compound, AML-101 is a newly discovered highly specific and selective agonist of a3- and-a5-GABAA agonist that has shown considerable activity against medulloblastoma. Here we show for the first time that AML-101 markedly potentiates TMZ activity against patient-derived GBM cells. Furthermore, employing microdialysis studies we simultaneously assessed the pharmacokinetics (PK) of AML-101 in the brain extracellular fluid and plasma in rats. Results suggested facile passage of the compound across the blood-brain barrier (BBB) and the oral bioavailability of AML-101 was 0.7. Thus, our PK studies strongly support further development of this compound based on the observation that it has excellent pharmacodynamic and PK properties to be an anti-GBM therapy. In parallel, my work focused on advancing efforts for repurposing letrozole (LTZ), a widely used drug in the treatment breast cancer, for the treatment of GBM. LTZ exhibits effective brain penetration, tumor localization and efficacy against C6 glioma cells in rat models. Employing patient-derived GBM lines, we assessed the influence of LTZ and TMZ on cell viability and neurosphere growth. Combination index analysis was performed to gain quantitative insights of this interaction. The interaction was deemed to be highly synergistic. LTZ co-treatment also significantly increased DNA damaging effects of TMZ. Addition of estradiol abrogated these effects. Additionally, in an ongoing innovative “window-of-opportunity” clinical trial, we were able to measure brain tumor concentrations of LTZ in excised tumor tissues from recurrent GBM patients pre-dosed with LTZ. In this dose escalation trial, LTZ doses were escalated from 2.5 to 15 mg. At a dose of 15 mg/day, the PK endpoint was met given that the projected steady state concentration exceeded the pre-determined threshold of 2 µM. No dose-limiting toxicities were attributed to LTZ. Correlative studies documented a sharp dose-related decrease in estradiol concentration in the surgically harvested tumor tissue. Furthermore, RNA-seq analyses of these LTZ treated tumor samples strongly suggest LTZ dose-dependent downregulation of oncogenes implicated in cell proliferation and upregulation of tumor suppression markers, providing important clues to develop synergistic combination of LTZ for GBM therapy. Overall, our studies have made a vital contribution by advancing the development of an early stage compound, AML-101 and an FDA approved drug, LTZ, as novel combination partners with TMZ for the treatment of GBM, one of the most fatal human ailments.

Published
2022

31. GABA(A) receptor activation drives GABARAP-Nix mediated autophagy to radiation-sensitize primary and brain-metastatic lung adenocarcinoma tumors.

Author

Bhattacharya D, Barille R, Toukam DK, Gawali VS, Kallay L, Ahmed T, Brown H, Rezvanian S, Karve A, Desai PB, Medvedovic M, Wang K, Ionascu D, Harun N, Wang C, Baschnagel AM, Kritzer JA, Cook JM, Pomeranz Krummel DA, and Sengupta S

Abstract

In non-small cell lung cancer (NSCLC) treatment, targeted therapies benefit only a subset of NSCLC, while radiotherapy responses are not durable and toxicity limits therapy. We find that a GABA(A) receptor activator, AM-101, impairs viability and clonogenicity of NSCLC primary and brain metastatic cells. Employing an ex vivo 'chip', AM-101 is as efficacious as the chemotherapeutic docetaxel, which is used with radiotherapy for advanced-stage NSCLC. In vivo , AM-101 potentiates radiation, including conferring a survival benefit to mice bearing NSCLC intracranial tumors. GABA(A) receptor activation stimulates a selective-autophagic response via multimerization of GABA(A) Receptor-Associated Protein (GABARAP), stabilization of mitochondrial receptor Nix, and utilization of ubiquitin-binding protein p62. A targeted-peptide disrupting Nix binding to GABARAP inhibits AM-101 cytotoxicity. This supports a model of GABA(A) receptor activation driving a GABARAP-Nix multimerization axis triggering autophagy. In patients receiving radiotherapy, GABA(A) receptor activation may improve tumor control while allowing radiation dose de-intensification to reduce toxicity., Highlights: Activating GABA(A) receptors intrinsic to lung primary and metastatic brain cancer cells triggers a cytotoxic response. GABA(A) receptor activation works as well as chemotherapeutic docetaxel in impairing lung cancer viability ex vivo . GABA(A) receptor activation increases survival of mice bearing lung metastatic brain tumors.A selective-autophagic response is stimulated by GABA(A) receptor activation that includes multimerization of GABARAP and Nix.Employing a new nanomolar affinity peptide that abrogates autophagosome formation inhibits cytotoxicity elicited by GABA(A) receptor activation.

Published
2023
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