Samantha Nichols
A5066240023- Lung Cancer Research Studies
- Lung Cancer Treatments and Mutations
- Cancer Genomics and Diagnostics
- Chronic Myeloid Leukemia Treatments
- RNA modifications and cancer
- Cancer therapeutics and mechanisms
- Colorectal Cancer Treatments and Studies
- PARP inhibition in cancer therapy
- Cancer Immunotherapy and Biomarkers
- Neuroendocrine Tumor Research Advances
- Epigenetics and DNA Methylation
- DNA Repair Mechanisms
- Acute Lymphoblastic Leukemia research
- Peptidase Inhibition and Analysis
- Pancreatic and Hepatic Oncology Research
- Neuroblastoma Research and Treatments
- Synthesis and pharmacology of benzodiazepine derivatives
- Biochemical and Molecular Research
- Chromatin Remodeling and Cancer
- Synthesis and Biological Evaluation
- Immune Cell Function and Interaction
- Higher Education Research Studies
- Innovations in Educational Methods
- Folate and B Vitamins Research
- Cancer Treatment and Pharmacology
Center for Cancer Research
2019-2025
National Cancer Institute
2018-2025
National Institutes of Health
2021-2024
Bowie State University
2023
Abstract Molecular subtypes of small cell lung cancer (SCLC) defined by the expression key transcription regulators have recently been proposed in lines and limited number primary tumors. The clinical biological implications neuroendocrine (NE) metastatic SCLC, extent to which they vary within between patient tumors patient-derived models is not known. We integrate histology, transcriptome, exome, treatment outcomes SCLC from a range sites, revealing complex intra- intertumoral heterogeneity...
Small-cell lung cancer (SCLC) is an aggressive neuroendocrine cancer. Oncogenic MYC amplifications drive SCLC heterogeneity, but the genetic mechanisms of amplification and phenotypic plasticity, characterized by nonneuroendocrine cell states, are not known. Here, we integrate whole-genome sequencing, long-range optical mapping, single-cell DNA fluorescence in situ hybridization to find extrachromosomal (ecDNA) as a primary source oncogene driver fusions. ecDNAs bring proximity enhancer...
Because tobacco is a potent carcinogen, secondary causes of lung cancer are often diminished in perceived importance. To assess the extent inherited susceptibility to small cell (SCLC), most lethal type cancer, we sequenced germline exomes 87 patients (77 SCLC and 10 extrapulmonary cell) considered 607 genes, discovering 42 deleterious variants 35 cancer-predisposition genes among 43.7% patients. These findings were validated an independent cohort 79 with SCLC. Loss heterozygosity was...
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...
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 Background Profiling circulating cell-free DNA (cfDNA) has become a fundamental practice in cancer medicine, but the effectiveness of cfDNA at elucidating tumor-derived molecular features not been systematically compared to standard single-lesion tumor biopsies prospective cohorts patients. The use plasma instead tissue guide therapy is particularly attractive for patients with small cell lung (SCLC), due aggressive clinical course this cancer, which makes obtaining exceedingly...
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)...
TPS8130 Background: Small-cell lung cancer (SCLC) is the most fatal type of characterized by exquisite chemo-sensitivity at diagnosis and chemoresistance relapse. Despite a highly mutated genome, patients with SCLC derive little benefit from immunotherapy. EZH2 (enhancer zeste homolog 2) master epigenetic regulator neuroendocrine cell fate plasticity. inhibition 1) promotes upregulation Schlafen 11 (SLFN11) which irreversibly blocks replication in response to DNA damaging agents enhances...
Abstract Emerging data on small cell lung cancer (SCLC), an aggressive malignancy with exceptionally poor prognosis, support subtypes driven by distinct transcription regulators, which engender unique therapeutic vulnerabilities. However, the translational potential of these observations is limited access to tumor biopsies. Here, we leverage chromatin immunoprecipitation cell-free nucleosomes carrying active modifications followed sequencing (cfChIP-seq) 442 plasma samples from individuals...
Abstract Alterations in the ATM gene are among most common somatic and hereditary cancer mutations, ATM-deficient tumors hypersensitive to DNA-damaging agents. A synthetic lethal combination of agents DNA repair inhibitors could have widespread utility cancers. However, overlapping normal tissue toxicities from these drug classes precluded their clinical translation. We investigated PLX038, a releasable polyethylene glycol-conjugate topoisomerase I inhibitor SN-38, wild-type null isogenic...
Abstract Despite provocative preclinical results, dose-limiting toxicities have precluded rational combinations of cytotoxic chemotherapies that increase DNA damage with response (DDR) inhibitors. We hypothesized tumor-targeted delivery chemotherapy might enable tolerable and active DDR conducted a phase I clinical trial combining ataxia telangiectasia Rad3-related (ATR) inhibitor berzosertib sacituzumab govitecan, trophoblast cell surface antigen 2 (Trop-2) directed antibody drug conjugate...
<p>Amplicon design used for the targeted single-cell copy-number analysis. Normalized depth of MYC and MYCL amplicons in single-cells DMS-273 cell line are shown, as well comparison amplicon depths single cells between patient derived Adrenal gland (ecDNA+) Cerv.LN (HSR+) lines.</p>
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...
Abstract Background Profiling circulating cell-free DNA (cfDNA) has become a fundamental practice in cancer medicine, but the effectiveness of cfDNA at elucidating tumor-derived molecular features not been systematically compared to standard single-lesion tumor biopsies prospective cohorts patients. The use plasma instead tissue guide therapy is particularly attractive for patients with small cell lung (SCLC), whose aggressive clinical course making it exceedingly challenging obtain...
<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>