Rasa Vilimas
A5000666931- Lung Cancer Research Studies
- Lung Cancer Treatments and Mutations
- Cancer Genomics and Diagnostics
- Chronic Myeloid Leukemia Treatments
- RNA modifications and cancer
- Colorectal Cancer Treatments and Studies
- PARP inhibition in cancer therapy
- Cancer therapeutics and mechanisms
- Cancer Immunotherapy and Biomarkers
- Neuroendocrine Tumor Research Advances
- Epigenetics and DNA Methylation
- Acute Lymphoblastic Leukemia research
- Pancreatic and Hepatic Oncology Research
- DNA Repair Mechanisms
- Heat shock proteins research
- Chromatin Remodeling and Cancer
- Soft tissue tumor case studies
- Immune Cell Function and Interaction
- Neuroblastoma Research and Treatments
- Cell death mechanisms and regulation
- Ovarian cancer diagnosis and treatment
- Tumors and Oncological Cases
- BRCA gene mutations in cancer
- Toxin Mechanisms and Immunotoxins
- Frailty in Older Adults
National Cancer Institute
2017-2025
Center for Cancer Research
2019-2025
National Institutes of Health
2017-2024
Office of the Director
2022
Leidos (United States)
2016-2017
Frederick National Laboratory for Cancer Research
2017
Leidos Biomedical Research Inc. (United States)
2016
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...
Purpose Desmoid tumors (aggressive fibromatosis) arise from connective tissue cells or fibroblasts. In general, they are slow growing and do not metastasize; however, locally aggressive desmoid can cause severe morbidity loss of function. Disease recurrence after surgery and/or radiation diagnosis multifocal highlight the need to develop effective systemic treatments for this disease. study, we evaluate objective response rate therapy with γ-secretase inhibitor PF-03084014 in patients...
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...
3515 Background: PEN-866 is a miniature drug conjugate which links HSP90 binding small molecule to SN-38 cytotoxic payload. highly expressed in advanced malignancies. targets and binds activated tumor protein, releases its payload, results complete regressions multiple xenograft models. This first-in-human study assessed safety, tolerability, pharmacokinetics (PK), preliminary efficacy of PEN-866. Methods: Patients (pts) with progressive, solid malignancies were enrolled escalating cohorts...
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...
11028 Background: Desmoids are rare, locally invasive, slow growing soft tissue tumors that either sporadic or associated with familial genetic syndromes such as adenomatous polyposis. characterized by stabilization and abnormal nuclear localization of β-catenin. Mutations in the CTNNB1 gene found 85-90% desmoids. Gamma-secretase cleaves intracellular Notch, resulting Notch signaling. PF-030844014 (PF) is an oral, reversible γ-secretase inhibitor was well tolerated a phase I trial. We report...
Abstract Background Multiple preclinical studies have shown cytotoxic synergy involving combinations of poly (ADP-ribose) polymerase (PARP) inhibitors and topoisomerase 1 (TOP1) inhibitors, but such proven too toxic in clinical trials. Liposomal irinotecan (nal-IRI) achieved similar intratumoral exposure with better antitumor activity than the conventional TOP1 inhibitor models. Tumor targeted delivery using nal-IRI an intermittent schedule administration PARP may provide a tolerable...
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...
e21153 Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) show variable clinical activity in individuals with advanced cancers. In the lung-MAP substudy S1400G, talazoparib alone was not sufficiently active squamous lung cancers homologous recombinant repair deficiency. Combinations of PARPi immune checkpoint (ICIs) are under investigation since preclinical studies an immunostimulatory effect that can potentially increase responsiveness to ICIs. To test this hypothesis, we evaluated...
<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 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>