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26 results on '"Ravikrishnan, Janani"'

1. VIP152 is a selective CDK9 inhibitor with pre-clinical in vitro and in vivo efficacy in chronic lymphocytic leukemia

Author

Sher, Steven, Whipp, Ethan, Walker, Janek, Zhang, Pu, Beaver, Larry, Williams, Katie, Orwick, Shelley, Ravikrishnan, Janani, Walker, Brandi, Perry, Elizabeth, Gregory, Charles, Purcell, Matthew, Pan, Alexander, Yan, Pearlly, Alinari, Lapo, Johnson, Amy J., Frigault, Melanie M., Greer, Joy M., Hamdy, Ahmed, Izumi, Raquel, Mo, Xiaokui, Sampath, Deepa, Woyach, Jennifer, Blachly, James, Byrd, John C., and Lapalombella, Rosa

Published
2023
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5. Enriched Signalling Pathways in Venetoclax-Relapsed Chronic Lymphocytic Leukemia (CLL) Cells and Targeting Using a Protac-Based Bcl-2/Bcl-Xl Degrader

Author

Diaz Rohena, Daisy, primary, Peris Cuesta, Arnau, additional, Slawin, Bailey, additional, Ravikrishnan, Janani, additional, Liu, Chaomei, additional, Williams, Charmelle, additional, Hu, Wanyi, additional, Zhang, Peiyi, additional, Thompson, Philip, additional, Wierda, William G., additional, Jain, Nitin, additional, Shukla, Sachet, additional, Zheng, Guangrong, additional, Zhou, Daohong, additional, Woyach, Jennifer A., additional, and Sampath, Deepa, additional

Published
2023
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7. PRMT5 Inhibition Alters Mitochondrial Dynamics in Mantle Cell Lymphoma Creating Vulnerability to BH3 Mimetic Compounds

Author

Hinterschied, Claire, primary, Brown, Fiona, additional, Ravikrishnan, Janani, additional, Helmig-Mason, JoBeth, additional, Harrison, Kaylee R., additional, Yasin, Aneeq, additional, Sloan, Shelby, additional, Long, Mackenzie, additional, Bhagwat, Neha, additional, Vaddi, Kris, additional, Scherle, Peggy, additional, Woyach, Jennifer A., additional, Chen-Kiang, Selina, additional, Elemento, Olivier, additional, Paik, Jihye, additional, and Baiocchi, Robert A., additional

Published
2022
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8. Targeting Venetoclax Resistant CLL Using a Protac-Based BCL-2/BCL-XL Degrader

Author

Diaz Rohena, Daisy, primary, Slawin, Bailey, additional, Ravikrishnan, Janani, additional, Liu, Chaomei, additional, Hu, Wanyi, additional, Zhang, Peiyi, additional, Thompson, Philip A., additional, Wierda, William G., additional, Jain, Nitin, additional, Zheng, Guangrong, additional, Zhou, Daohong, additional, Woyach, Jennifer A., additional, and Sampath, Deepa, additional

Published
2022
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9. MS-553, a Selective PKC-ß Inhibitor Inhibits BCR Signaling and Synergizes with Venetoclax for the Treatment of High Risk CLL

Author

Singh, Jyotsana, primary, Diaz Rohena, Daisy, additional, Liu, Chaomei, additional, Slawin, Bailey, additional, Ravikrishnan, Janani, additional, Jain, Nitin, additional, Wierda, William G., additional, Zhang, Kai, additional, Niesman, Michael, additional, Woyach, Jennifer A., additional, and Sampath, Deepa, additional

Published
2022
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10. VIP152 is a selective CDK9 inhibitor with pre-clinical in vitro and in vivo efficacy in chronic lymphocytic leukemia

Author

Sher, Steven, primary, Whipp, Ethan, additional, Walker, Janek, additional, Zhang, Pu, additional, Beaver, Larry, additional, Williams, Katie, additional, Orwick, Shelley, additional, Ravikrishnan, Janani, additional, Walker, Brandi, additional, Perry, Elizabeth, additional, Gregory, Charles, additional, Purcell, Matthew, additional, Pan, Alexander, additional, Yan, Pearlly, additional, Alinari, Lapo, additional, Johnson, Amy J., additional, Frigault, Melanie M., additional, Greer, Joy M., additional, Hamdy, Ahmed, additional, Izumi, Raquel, additional, Mo, Xiaokui, additional, Sampath, Deepa, additional, Woyach, Jennifer, additional, Blachly, James, additional, Byrd, John C., additional, and Lapalombella, Rosa, additional

Published
2022
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11. Abstract 1031: PRMT5 inhibition alters mitochondrial dynamics in mantle cell lymphoma, creating vulnerability to BH3 mimetic compounds

Author

Hinterschied, Claire, primary, Brown, Fiona, additional, Ravikrishnan, Janani, additional, Helmig-Mason, JoBeth, additional, Vaddi, Kris, additional, Scherle, Peggy, additional, Woyach, Jennifer, additional, Chen-Kiang, Selina, additional, Elemento, Oliver, additional, Paik, Jihye, additional, and Baiocchi, Robert, additional

Published
2022
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12. Additional file 1 of Preclinical evaluation of combination nemtabrutinib and venetoclax in chronic lymphocytic leukemia

Author

Muhowski, Elizabeth M., Ravikrishnan, Janani, Gordon, Britten, Yu, Lianbo, Misra, Shrilekha, Walker, Brandi, Eathiraj, Sudharshan, Sampath, Deepa, Rogers, Kerry A., Byrd, John C., and Woyach, Jennifer A.

Abstract

Additional file 1: Fig. S1. Kaplan–Meier estimated survival of all recipient mice (n=93) treated with vehicle, venetoclax (100 mg/kg), nemtabrutinib (75 mg/kg), ibrutinib (25 mg/kg), venetoclax (100 mg/kg) and nemtabrutinib (75 mg/kg), or venetoclax (100 mg/kg) and ibrutinib (25 mg/kg).

Published
2022
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13. HDAC1 regulates the chromatin landscape to control transcriptional dependencies in chronic lymphocytic leukemia

Author

Lai, Tzung-Huei, Ozer, Hatice Gulcin, Gasparini, Pierluigi, Nigita, Giovanni, Distefano, Rosario, Yu, Lianbo, Ravikrishnan, Janani, Yilmaz, Selen, Gallegos, Juan, Shukla, Sachet, Puduvalli, Vinay, Woyach, Jennifer, Lapalombella, Rosa, Blachly, James, Byrd, John C., and Sampath, Deepa

Abstract

•HDAC1 is recruited at SEs to transcriptionally activate driver genes in CLL. In the absence of SEs, HDAC1 silences gene expression.•The transcriptional activator and repressor functions of HDACs cooperate to establish transcriptional dependencies in CLL.

Published
2023
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14. Characterization of LP-118, a Novel Small Molecule Inhibitor of Bcl-2 and Bcl-Xl in Chronic Lymphocytic Leukemia Resistant to Venetoclax

Author

Ravikrishnan, Janani, primary, Muhowski, Elizabeth M., additional, Lai, Tzung-Huei, additional, Misra, Shrilekha, additional, Diaz Rohena, Daisy, additional, Tan, Felai, additional, Chen, Yi, additional, Anthony, Stephen P., additional, Chen, Yu, additional, Shen, Yue, additional, Byrd, John C., additional, Sampath, Deepa, additional, and Woyach, Jennifer A., additional

Published
2021
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15. Targeting Venetoclax-Resistant CLL By Bcl-XL Degradation

Author

Diaz Rohena, Daisy, primary, Ravikrishnan, Janani, additional, Liu, Chaomei, additional, Zheng, Guangrong, additional, Zhou, Daohong, additional, Zhang, Peiyi, additional, Wierda, William G., additional, Jain, Nitin, additional, Woyach, Jennifer A., additional, and Sampath, Deepa, additional

Published
2021
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16. The PKC-β Inhibitor MS-553 Displays Preclinical Efficacy in BTK Inhibitor Resistant Chronic Lymphocytic Leukemia

Author

Gordon, Britten, Muhowski, Elizabeth, Ravikrishnan, Janani, Thangavadivel, Shanmugapriya, Benrashid, Samon, He, Alexander, Misra, Shrilekha, Lai, Tzung-Huei, Marr, Alexander, Yu, Lianbo, Walker, Brandi, Perry, Elizabeth, Grieselhuber, Nicole R., Rogers, Kerry A, Blachly, James S., Kittai, Adam S, Bhat, Seema A, Byrd, John C., Niesman, Michael, Zhang, Kai, Sampath, Deepa, and Woyach, Jennifer A.

Published
2023
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17. Targeting Covalent and Non-Covalent Btki-Resistant CLL Using the Dual Irreversible/Reversible 4 th Generation BTK Inhibitor LP-168

Author

Gordon, Britten, Muhowski, Elizabeth, Ravikrishnan, Janani, Benrashid, Samon, Mitchell, Andrew, He, Alexander, Misra, Shrilekha, Lai, Tzung-Huei, Thangavadivel, Shanmugapriya, Marr, Alexander, Yu, Lianbo, Walker, Brandi, Perry, Elizabeth, Rogers, Kerry A, Kittai, Adam S, Bhat, Seema A, Byrd, John C., Sampath, Deepa, Lapalombella, Rosa, Han, Weiguo, Kay, Neil E., Chen, Yi, Tan, Fenlai, Anthony, Stephen P., Chen, Yu, and Woyach, Jennifer A.

Published
2023
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18. HDAC1 regulates the chromatin landscape to establish transcriptional dependencies in chronic lymphocytic leukemia

Author

Lai, Tzung-Huei, primary, Ozer, Hatice Gulcin, additional, Gasparini, Pierluigi, additional, Nigita, Giovanni, additional, Destefano, Rosario, additional, Yu, Lianbo, additional, Ravikrishnan, Janani, additional, Tsai, Tzung-Lin, additional, Lapalombella, Rosa, additional, Woyach, Jennifer, additional, Puduvalli, Vinay, additional, Blachly, James, additional, Byrd, John C, additional, and Sampath, Deepa, additional

Published
2020
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19. Role of Mutant p53 in the Progression of Chronic Lymphocytic Leukemia

Author

Ravikrishnan, Janani, primary, Lai, Tzung-Huei, additional, Muhowski, Elizabeth, additional, Brinton, Lindsey, additional, Williams, Katie, additional, Thompson, Alexandria, additional, Blachly, James S., additional, Ozer, Hatice Gulcin, additional, Byrd, John C., additional, Lapalombella, Rosa, additional, Woyach, Jennifer, additional, and Sampath, Deepa, additional

Published
2019
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21. HSP90 inhibition depletes DNA repair proteins to sensitize acute myelogenous leukemia to nucleoside analog chemotherapeutics

Author

Lai, Tzung-Huei, primary, Mitchell, Shaneice, additional, Wu, Pei-Jung, additional, Orwick, Shelley, additional, Liu, Chaomei, additional, Ravikrishnan, Janani, additional, Woyach, Jennifer, additional, Mims, Alice, additional, Plunkett, William, additional, Puduvalli, Vinay K., additional, Byrd, John C., additional, Lapalombella, Rosa, additional, and Sampath, Deepa, additional

Published
2019
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22. Using HSP90 Inhibitors to Target DNA Repair Proteins in AML

Author

Ravikrishnan, Janani, primary, Lai, Tzung-Huei, additional, Mitchell, Shaneice Renee, additional, Wu, Pei-Jung, additional, Orwick, Shelley, additional, Liu, Chaomei, additional, Woyach, Jennifer A., additional, Mims, Alice S., additional, Plunkett, William, additional, Puduvalli, Vinay K, additional, Byrd, John C., additional, Lapalombella, Rosa, additional, and Sampath, Deepa, additional

Published
2018
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24. Targeting Covalent and Non-Covalent Btki-Resistant CLL Using the Dual Irreversible/Reversible 4 thGeneration BTK Inhibitor LP-168

Author

Gordon, Britten, Muhowski, Elizabeth, Ravikrishnan, Janani, Benrashid, Samon, Mitchell, Andrew, He, Alexander, Misra, Shrilekha, Lai, Tzung-Huei, Thangavadivel, Shanmugapriya, Marr, Alexander, Yu, Lianbo, Walker, Brandi, Perry, Elizabeth, Rogers, Kerry A, Kittai, Adam S, Bhat, Seema A, Byrd, John C., Sampath, Deepa, Lapalombella, Rosa, Han, Weiguo, Kay, Neil E., Chen, Yi, Tan, Fenlai, Anthony, Stephen P., Chen, Yu, and Woyach, Jennifer A.

Abstract

Background:Treatment of chronic lymphocytic leukemia (CLL) has been transformed with targeted therapies including inhibitors of Bruton's tyrosine kinase (BTKi). Currently three covalent BTK inhibitors (cBTKi) are approved for CLL, but most patients eventually relapse, commonly through acquisition of the C481S BTK mutation (Woyach et al.2014). Pirtobrutinib and nemtabrutinib are non-covalent BTK inhibitors (ncBTKi) developed to target and inhibit C481S mutant BTK. However novel secondary site mutations in BTK, namely T474I and L528W, have been found to confer resistance to both cBTKi and ncBTKi (Wang et al.2022). Regardless of these mutations, BCR signaling remains intact, suggesting that inhibition of BTK maintains its therapeutic importance. LP-168 is a novel ultra-selective 4 thgeneration BTKi with an active warhead capable of covalent interaction with WT BTK or non-covalent binding when a BTK C481 mutation is present.

Published
2023
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25. Targeted Therapies for High-Risk Chronic Lymphocytic Leukemia

Author

Ravikrishnan, Janani

Subjects
Biomedical Research, Chronic Lymphocytic Leukemia, CLL, targeted therapies, venetoclax resistance, p53, TP53 mutations
Abstract

Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia and is characterized by the accumulation of mature CD19+CD5+ B cells that acquire a variety of chromosomal and genomic aberrations. This gives rise to many advantages to CLL cells including the ability to have enhanced proliferation and be resistant to apoptosis. These discoveries led to the development of targeted therapies for these aberrant pathways including Brutons Tyrosine kinase (BTK) inhibitor, ibrutinib, and B cell lymphoma 2 (BCL-2) inhibitor, venetoclax. However, even with targeted therapies, some subgroups of the CLL patients classified as high-risk need treatment for progressive disease or have genomic aberrations that lead to a poor outcome. One such group are patients with a deletion of chromosome 17 (del17p) leading to the loss of one allele of tumor suppressor protein TP53. This occurs in about 10% of patients at diagnosis and increases to 30% in relapsed/refractory disease. Additionally, about 83% of patients with a del17p acquire a mutation on their second TP53 allele at one of several sites within the DNA binding domain. Little is known of the role of these “hotspot” mutations (e.g., R175H, R248Q/W, R273H) in CLL. Clinically, patients with del17p/mutant p53 have worse survival, disease progression, and frequently relapse on targeted therapies such as ibrutinib. While relapse to ibrutinib is mainly caused by acquired mutations in BTK or its downstream target PLCγ2, we hypothesized that CLL with mutant p53 is a key driver of resistance and progression. To investigate this, we utilized the techniques of RNA sequencing RNA-seq and chromatin immunoprecipitation sequencing (ChIP-seq) to uncover unique transcriptionally regulated targets of mutant p53 in CLL. We identified two key proteins that are potential key downstream effectors of CLL patient cells with mutant p53, BCL2L1 (BCL-xL), and PRKCB (PKC-β). To determine whether mutations in p53 were causal in the observed increases in PKC-β and Bcl-xL, we used CRISPR-Cas9 editing to introduce mutations at R175H and R248Q in the p53 wildtype CLL cell lines HG-3. We used a novel inhibitor of PKC-β, MS-553 and we show that targeting mutant p53 with MS-553 can be a successful strategy at abrogating the downstream signaling pathway.We continued our investigation into another high-risk group of CLL patients who are relapsed/refractory (R/R) to BCL-2 inhibitor, venetoclax. By utilizing the technique of BH3 profiling on venetoclax R/R cells we found cells to have dependencies on anti-apoptotic proteins BCL-2 and BCL-xL, therefore, providing a rationale for dual inhibition of BCL-2/BCL-xL. We performed pre-clinical investigations of LP-118, a novel small molecule inhibitor of BCL-2, more potent than venetoclax and with decreased binding to BCL-xL to minimize platelet toxicity. Collectively, our in vitro studies demonstrated preclinical efficacies of LP-118 in primary CLL samples resistant to venetoclax and BCL-2 G101V mutant cells. Additional in vivo work has further confirmed the efficacy of LP-118 in vivo in BCL-2 mutant cell lines. This work justifies continued preclinical and clinical work with this agent, and a phase 1 first-in-human study will begin in patients with relapsed hematologic malignancies (NCT04771572).

Published
2022

26. LP-118 is a novel B-cell lymphoma 2 / extra-large inhibitor that demonstrates efficacy in models of venetoclax-resistant chronic lymphocytic leukemia.

Author

Ravikrishnan J, Diaz-Rohena DY, Muhowski E, Mo X, Lai TH, Misra S, Williams CD, Sanchez J, Mitchell A, Satpati S, Perry E, Kaufman T, Liu C, Lozanski A, Lozanski G, Rogers K, Kittai AS, Bhat SA, Collins MC, Davids MS, Jain N, Wierda WG, Lapalombella R, Byrd JC, Tan F, Chen Y, Chen Y, Shen Y, Anthony SP, Woyach JA, and Sampath D

Abstract

Patients with chronic lymphocytic leukemia (CLL) respond well to initial treatment with the Bcell lymphoma 2 (BCL2) inhibitor venetoclax. Upon relapse, they often retain sensitivity to BCL2 targeting, but durability of response remains a concern. We hypothesize that targeting both BCL2 and B-cell lymphoma-extra large (BCLXL) will be a successful strategy to treat CLL, including for patients who relapse on venetoclax. To test this hypothesis, we conducted a pre-clinical investigation of LP-118, a highly potent inhibitor of BCL2 with moderate BCLXL inhibition to minimize platelet toxicity. This study demonstrated that LP-118 induces efficient BAK activation, cytochrome C release, and apoptosis in both venetoclax naïve and resistant CLL cells. Significantly, LP-118 is effective in cell lines expressing the BCL2 G101V mutation and in cells expressing BCLXL but lacking BCL2 dependence. Using an immunocompetent mouse model, Eμ-TCL1, LP-118 demonstrates low platelet toxicity, which hampered earlier BCLXL inhibitors. Finally, LP-118 in the RS4;11 and OSU-CLL xenograft models results in decreases in tumor burden and survival advantage, respectively. These results provide a mechanistic rationale for the evaluation of LP-118 for the treatment of venetoclax responsive and relapsed CLL.

Published
2024
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