Biology subjects

Kenchappa, R.

Publications and source records attributed to Kenchappa, R..

4 recordsLinked to original sources

bioRxiv2026

Microtubule Acetylation Regulates the Malignant Phenotype of Glioblastoma and is a Promising Therapeutic Target

Glioblastoma (GBM) is universally lethal despite decades of research to find effective treatments. This highlights the need to identify druggable targets essential for sustaining the malignant phenotype but dispensable for normal tissue. We propose that the enzyme -tubulin acetyl transferase (ATAT1) meets these criteria. ATAT1 acetylates -tubulin at lysine 40, which increases microtubule stability and promotes microtubule-based transport. While ATAT1 knockout mice have only a very mild phenotype, ATAT1 suppression in GBM has multiple therapeutic effects by reducing tumor invasion, proliferation, and therapeutic resistance. These translate not only into improved survival with ATAT1 targeting by itself, but also into synergy when ATAT1 deletion is combined with FDA approved therapies. This study strongly supports our conclusion that ATAT1 is a promising therapeutic target in GBM.

Cancer Biology↗

bioRxiv2024

Virtual Clinical Trials of BMP4 Differentiation Therapy: Digital Twins to Aid Glioblastoma Trial Design

Glioma stem cells (GSCs) are considered a major driver of glioblastoma (GBM) progression and are highly resistant to standard cytotoxic treatments. BMP4 has been shown to drive differentiation of GSCs, increase sensitivity to radiotherapy, slow growth and increase survival times in animal models. To assess the potential of BMP4 as a differentiation therapy, we develop a mathematical model that describes the growth of a GBM tumor via a hierarchy of GSCs, progenitor cells and terminally differentiated cells. We parametrize our model using experimental data from twelve patient-derived GSC lines, on which we measured response to radiotherapy and population growth with and without exposure to BMP4. Cell lines were typically more sensitive to radiotherapy after two days of BMP4 treatment but population growth can either increase or decrease after seven days of exposure to BMP4. To identify key parameters that drive successful treatment we perform global sensitivity analysis which identifies key parameters for BMP4 efficacy including proliferation rate and self-renewal sensitivity of GSCs. We then compare two treatment schedules: a single dose of BMP4 at resection and continuous delivery of BMP4 from resection till the end of radiotherapy. Due to the short half-life of BMP4 and its synergy with radiotherapy, continuous delivery of BMP4 during radiotherapy is more effective than a single dose prior to radiotherapy. We then perform a series of virtual clinical trials, stratified by tumor proliferation rate and GSC self-renewal sensitivity, which allows us to estimate the probability of observing a successful early-phase clinical trial for various virtual patient cohorts. We find that trials that selected the subset of patients with more proliferative GBMs were more likely to lead to significant improvements in survival. SignificanceTargeting glioma stem cells with BMP4 provides a novel opportunity to shift the complex cellular ecosystem of gliomas to enhance treatment efficacy. Mathematical modelling can facilitate optimal patient tumor feature selection when designing successful clinical trials.

cancer biology↗

bioRxiv2024

Resistance to Spindle Inhibitors in Glioblastoma Depends on STAT3 and Therapy Induced Senescence

While mitotic spindle inhibitors specifically kill proliferating tumor cells without the toxicities of microtubule poisons, resistance has limited their clinical utility. Treating glioblastomas with the spindle inhibitors ispinesib, alisertib, or volasertib creates a subpopulation of therapy induced senescent cells that resist these drugs by relying upon the anti-apoptotic and metabolic effects of activated STAT3. Furthermore, these senescent cells expand the repertoire of cells resistant to these drugs by secreting an array of factors, including TGF{beta}, which induce proliferating cells to exit mitosis and become quiescent--a state that also resists spindle inhibitors. Targeting STAT3 restores sensitivity to each of these drugs by depleting the senescent subpopulation and inducing quiescent cells to enter the mitotic cycle. These results support a therapeutic strategy of targeting STAT3-dependent therapy-induced senescence to enhance the efficacy of spindle inhibitors for the treatment of glioblastoma. Highlights* Resistance to non-microtubule spindle inhibitors limits their efficacy in glioblastoma and depends on STAT3. * Resistance goes hand in hand with development of therapy induced senescence (TIS). * Spindle inhibitor resistant glioblastomas consist of three cell subpopulations--proliferative, quiescent, and TIS--with proliferative cells sensitive and quiescent and TIS cells resistant. * TIS cells secrete TGF{beta}, which induces proliferative cells to become quiescent, thereby expanding the population of resistant cells in a spindle inhibitor resistant glioblastoma * Treatment with a STAT3 inhibitor kills TIS cells and restores sensitivity to spindle inhibitors.

cancer biology↗

bioRxiv2024

MT-125 Inhibits Non-Muscle Myosin IIA and IIB, Synergizes with Oncogenic Kinase Inhibitors, and Prolongs Survival in Glioblastoma

We have identified a NMIIA and IIB-specific small molecule inhibitor, MT-125, and have studied its effects in GBM. MT-125 has high brain penetrance and retention and an excellent safety profile; blocks GBM invasion and cytokinesis, consistent with the known roles of NMII; and prolongs survival as a single agent in murine GBM models. MT-125 increases signaling along both the PDGFR- and MAPK-driven pathways through a mechanism that involves the upregulation of reactive oxygen species, and it synergizes with FDA-approved PDGFR and mTOR inhibitors in vitro. Combining MT-125 with sunitinib, a PDGFR inhibitor, or paxalisib, a combined PI3 Kinase/mTOR inhibitor significantly improves survival in orthotopic GBM models over either drug alone, and in the case of sunitinib, markedly prolongs survival in [~]40% of mice. Our results provide a powerful rationale for developing NMII targeting strategies to treat cancer and demonstrate that MT-125 has strong clinical potential for the treatment of GBM. HighlightsO_LIMT-125 is a highly specific small molecule inhibitor of non-muscle myosin IIA and IIB, is well-tolerated, and achieves therapeutic concentrations in the brain with systemic dosing. C_LIO_LITreating preclinical models of glioblastoma with MT-125 produces durable improvements in survival. C_LIO_LIMT-125 stimulates PDGFR- and MAPK-driven signaling in glioblastoma and increases dependency on these pathways. C_LIO_LICombining MT-125 with an FDA-approved PDGFR inhibitor in a mouse GBM model synergizes to improve median survival over either drug alone, and produces tumor free, prolonged survival in over 40% of mice. C_LI

cancer biology↗