Manan Krishnamurthy
A5032123069- Chronic Myeloid Leukemia Treatments
- Colorectal Cancer Treatments and Studies
- Cancer therapeutics and mechanisms
- Cancer Immunotherapy and Biomarkers
- PARP inhibition in cancer therapy
- Lung Cancer Treatments and Mutations
- Lung Cancer Research Studies
- DNA Repair Mechanisms
- Neuroendocrine Tumor Research Advances
- Estrogen and related hormone effects
- RNA Research and Splicing
- Hormonal Regulation and Hypertension
- Acute Lymphoblastic Leukemia research
- CRISPR and Genetic Engineering
- Immune Cell Function and Interaction
- Steroid Chemistry and Biochemistry
- Plant Genetic and Mutation Studies
- RNA and protein synthesis mechanisms
- interferon and immune responses
- Mitochondrial Function and Pathology
- Nuclear Structure and Function
- ATP Synthase and ATPases Research
- Genetics and Neurodevelopmental Disorders
- Pancreatic and Hepatic Oncology Research
- Chromatin Remodeling and Cancer
National Institutes of Health
2022-2025
National Cancer Institute
2022-2025
Tufts University
2021-2025
Icahn School of Medicine at Mount Sinai
2024-2025
Center for Cancer Research
2023-2024
Mount Sinai Hospital
2024
Abstract DNA polymerase theta (Pol θ) is an error-prone translesion that becomes crucial for double-strand break repair when cells are deficient in homologous recombination or non-homologous end joining. In some organisms, Pol θ also promotes tolerance of interstrand crosslinks. Due to its importance damage tolerance, emerging target treatment cancer and disease. Prior work has characterized the functions helicase-like domains, but roles linker domain largely unknown. Here, we show...
Patients with relapsed small cell lung cancer (SCLC), a high replication stress tumor, have poor prognoses and few therapeutic options. A phase 2 study showed antitumor activity the addition of ataxia telangiectasia Rad3-related kinase inhibitor berzosertib to topotecan.
Despite promising preclinical studies, toxicities have precluded combinations of chemotherapy and DNA damage response (DDR) inhibitors. We hypothesized that tumor-targeted delivery might enable clinical translation such combinations.In a phase I trial, we combined sacituzumab govitecan, antibody-drug conjugate (ADC) delivers topoisomerase-1 inhibitor SN-38 to tumors expressing Trop-2, with ataxia telangiectasia Rad3-related (ATR) berzosertib. Twelve patients were enrolled across three dose...
Abstract Small‐cell lung cancer (SCLC) is the most lethal type of cancer. Specifically, MYC‐driven non‐neuroendocrine SCLC particularly resistant to standard therapies. Lurbinectedin was recently approved for treatment relapsed SCLC, but combinatorial approaches are needed increase depth and duration responses lurbinectedin. Using high‐throughput screens, we found inhibitors ataxia telangiectasia mutated rad3 related (ATR) as effective agents augmenting lurbinectedin efficacy. First‐in‐class...
The glucocorticoid and mineralocorticoid receptors (GR MR, respectively) have distinct, yet overlapping physiological pathophysiological functions. There are indications that both interact functionally physically, but the precise role of this interdependence is poorly understood. Here, we analyzed impact GR coexpression on MR genome-wide transcriptional responses chromatin binding upon activation by aldosterone glucocorticoids, ligands receptor. Transcriptional in absence result fewer...
Small-cell lung cancer (SCLC) is the most fatal form of cancer. Intratumoral heterogeneity, marked by neuroendocrine (NE) and non-neuroendocrine (non-NE) cell states, defines SCLC, but cell-extrinsic drivers SCLC plasticity are poorly understood. To map landscape tumor microenvironment (TME), we apply spatially resolved transcriptomics quantitative mass spectrometry-based proteomics to metastatic tumors obtained via rapid autopsy. The phenotype overall composition non-malignant cells in TME...
Abstract Metastasis is the leading cause of cancer-related deaths, yet its regulatory mechanisms are not fully understood. Small-cell lung cancer (SCLC) most metastatic form cancer, with patients presenting widespread disease, making it an ideal model for studying metastasis. However, lack suitable preclinical models has limited such studies. We utilized well-annotated rapid autopsy-derived tumors to develop xenograft that mimic key features SCLC, including histopathology, and development...
Abstract Lamin A/C (LMNA), a key component of the nuclear envelope, plays an essential role in maintaining integrity and regulating genome organization. While LMNA dysregulation has been linked to genomic instability both cancer aging, specific mechanisms remain poorly understood. We investigated small cell lung (SCLC), highly lethal form characterized by neuroendocrine (NE) differentiation, low expression, extreme instability. show that depletion leads increased R-loop formation,...
Abstract Lamin A/C ( LMNA ), a key component of the nuclear envelope, is essential for maintaining integrity and genome organization [1]. While dysregulation has been implicated in genomic instability across cancer aging, underlying mechanisms remain poorly understood [2]. Here, we investigate ’s role small-cell lung (SCLC), highly aggressive malignancy characterized by extreme [3, 4]. We demonstrate that depletion promotes R-loop accumulation, transcription-replication conflicts,...
Abstract While the cohesin complex is a key player in genome architecture, how it localizes to specific chromatin sites not understood. Recently, we and others have proposed that direct interactions with transcription factors lead localization of cohesin-loader (NIPBL/MAU2) within enhancers. Here, identify two clusters LxxLL motifs NIPBL sequence regulate dynamics, interactome, NIPBL-dependent transcriptional programs. One these interacts MAU2 necessary for maintenance NIPBL–MAU2...
The glucocorticoid and mineralocorticoid receptors (GR MR, respectively) have distinct, yet overlapping physiological pathophysiological functions. There are indications that both interact functionally physically, but the precise role of this interdependence is poorly understood. Here, we analyzed impact GR co-expression on MR genome-wide chromatin binding transcriptional responses to aldosterone glucocorticoids, ligands receptor. Our data show alters consensus DNA sequences in a locus-...
Summary Small-cell lung cancer (SCLC) is the most fatal form of cancer. Intra-tumoral heterogeneity, marked by neuroendocrine (NE) and non-neuroendocrine (non-NE) cell states, defines SCLC, but drivers SCLC plasticity are poorly understood. To map landscape tumor microenvironment (TME), we apply spatially resolved transcriptomics quantitative mass spectrometry-based proteomics to metastatic tumors obtained via rapid autopsy. The phenotype overall composition non-malignant cells in (TME)...
Abstract DNA polymerase theta (Pol θ) is an error-prone translesion that becomes crucial for double-strand break repair when cells are deficient in homologous recombination or non-homologous end joining. In some organisms, Pol θ also promotes tolerance of interstrand crosslinks. Due to its importance damage tolerance, emerging target treatment cancer and disease. Prior work has characterized the functions helicase-like domains, but roles linker domain largely unknown. Here, we show...
Abstract Background: Small cell lung cancer (SCLC) is the most aggressive type of cancer. Current therapies have limited efficacy in SCLC, and despite a highly mutated genome, SCLC largely unresponsive to immunotherapy. We sought leverage immune surveillance triggered by DNA damage patients with relapsed using bintrafusp alfa, bifunctional fusion protein targeting both PD-L1 TGF-beta. Hyperprogressive disease (HPD), characterized rapid acceleration tumor growth, has been reported...
<p>Comparison of treatment-related adverse events with the combination berzosertib and topotecan</p>
<p>Pharmacokinetic assessment</p>
<p>Trial protocol dose limiting toxicity criteria</p>
<p>Berzosertib pharmacodynamic assessment</p>
<p>PK results vs toxicity</p>
<p>Trial protocol dose limiting toxicity criteria</p>
<p>Berzosertib pharmacodynamic assessment</p>
<p>Pharmacokinetic assessment</p>