Early drivers of clonal hematopoiesis shape the evolutionary trajectories of acute myeloid leukemia.

Mutations commonly found in AML such as , and can be found in the peripheral blood of otherwise healthy adults - a phenomenon referred to as clonal hematopoiesis (CH). These mutations are thought to represent the earliest genetic events in the evolution of AML. Genomic studies on samples acquired at diagnosis, remission, and at relapse have demonstrated significant stability of CH mutations following induction chemotherapy.

Functional proteomics interrogation of the kinome identifies MRCKA as a therapeutic target in high-grade serous ovarian carcinoma.

High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecological cancer with few effective, targeted therapies. HGSOC tumors exhibit genomic instability with frequent alterations in the protein kinome; however, only a small fraction of the kinome has been therapeutically targeted in HGSOC. Using multiplexed inhibitor beads and mass spectrometry, we mapped the kinome landscape of HGSOC tumors from patients and patient-derived xenograft models.

Clonal Selection with RAS Pathway Activation Mediates Secondary Clinical Resistance to Selective FLT3 Inhibition in Acute Myeloid Leukemia.

Gilteritinib is a potent and selective kinase inhibitor with single-agent clinical efficacy in relapsed/refractory -mutated acute myeloid leukemia (AML). In this context, however, gilteritinib is not curative, and response duration is limited by the development of secondary resistance. To evaluate resistance mechanisms, we analyzed baseline and progression samples from patients treated on clinical trials of gilteritinib.

Analysis of T cell receptor repertoire based on Vβ chain in patients with breast cancer.

To find out if the T cell repertoire is efficiently and specifically provoked in patients with breast cancer, we have investigated the clonotypes of main T cell subsets (based on Vβ-Chain) in tumor draining lymph nodes. CD4+ helper, CD8+ cytotoxic and (CD4+CD127dimCD25+) regulatory T cells, were negatively selected, and isolated, from lymph node mononuclear cells of 14 untreated patients with breast cancer. Four non-malignant patients, who underwent surgical operation, were also recruited as the control group.

Preclinical rationale for combination of crizotinib with mitomycin C for the treatment of advanced colorectal cancer.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths in the United States. We analyzed 26 MSI-High and 558 non-MSI-High CRC tumors. BRCA2 mutations were highly enriched (50%) in MSI-High CRC.

BRCA2, EGFR, and NTRK mutations in mismatch repair-deficient colorectal cancers with MSH2 or MLH1 mutations.

Deficient mismatch repair (MMR) and microsatellite instability (MSI) contribute to ~15% of colorectal cancer (CRCs). We hypothesized MSI leads to mutations in DNA repair proteins including BRCA2 and cancer drivers including EGFR. We analyzed mutations among a discovery cohort of 26 MSI-High (MSI-H) and 558 non-MSI-H CRCs profiled at Caris Life Sciences.