A5046660353- Advanced Breast Cancer Therapies
- PI3K/AKT/mTOR signaling in cancer
- Lung Cancer Treatments and Mutations
- HER2/EGFR in Cancer Research
- Cancer Treatment and Pharmacology
- Chronic Lymphocytic Leukemia Research
- Cancer Genomics and Diagnostics
- Synthesis and biological activity
- Colorectal Cancer Treatments and Studies
- Estrogen and related hormone effects
- Cell death mechanisms and regulation
- Cancer-related Molecular Pathways
- Breast Cancer Treatment Studies
- Cancer Immunotherapy and Biomarkers
- Computational Drug Discovery Methods
- Pancreatic and Hepatic Oncology Research
- Gallbladder and Bile Duct Disorders
- Chronic Myeloid Leukemia Treatments
- Research on Leishmaniasis Studies
- Lung Cancer Research Studies
- Cancer, Hypoxia, and Metabolism
- Melanoma and MAPK Pathways
- Cancer Cells and Metastasis
- Molecular Biology Techniques and Applications
- Gene expression and cancer classification
National Institute for Health Research
2025
National Institute of Allergy and Infectious Diseases
2020-2023
Vector (United States)
2020-2023
National Institutes of Health
2020-2023
Colorado School of Mines
2014-2022
Roivant Sciences (United States)
2022
NanoImaging Services
2022
Icahn School of Medicine at Mount Sinai
2020
Memorial Sloan Kettering Cancer Center
2020
Cornell University
2020
Abstract Selective kinase inhibitors have emerged as an important class of cancer therapeutics, and several such drugs are now routinely used to treat advanced-stage disease. However, their clinical benefit is typically short-lived because the relatively rapid acquisition drug resistance following treatment response. Accumulating preclinical data point a role for heterogeneous response within subpopulation tumor cells that intrinsically drug-resistant, stem cells. We previously described...
Abstract Mutations in ESR1 have been associated with resistance to aromatase inhibitor (AI) therapy patients ER+ metastatic breast cancer. Little is known of the impact these mutations receiving selective oestrogen receptor degrader (SERD) therapy. In this study, hotspot and PIK3CA from ctDNA were assayed clinical trial samples cancer randomized either SERD fulvestrant or plus a pan-PI3K inhibitor. are present 37% baseline enriched luminal A -mutated tumours. often polyclonal longitudinal...
Seeing double can be a good thing Many human breast cancers harbor activating mutations in PIK3CA , the gene coding for catalytic subunit of phosphoinositide 3-kinase (PI3K). Clinical trials are underway to evaluate efficacy PI3K inhibitors cancer patients. Vasan et al. found unexpectedly that subset not one—but two— mutations, and occur on same allele (see Perspective by Toker). In model systems, hyperactivate signaling enhance tumor growth. Preliminary analysis clinical trial data suggests...
Abstract Neurotrophic tropomyosin receptor kinase ( NTRK) gene fusions are rare oncogenic drivers in solid tumours. This study aimed to interrogate a large real-world database of comprehensive genomic profiling data describe the landscape and prevalence NTRK fusions. fusion-positive tumours were identified from FoundationCORE ® >295,000 cancer patients. We investigated concomitant fusions, predicted patient ancestry compared cohort with entrectinib clinical trial cohorts (ALKA-372-001...
Abstract Purpose: Entrectinib potently inhibits tropomyosin receptor kinases (TRKAs)/B/C and ROS1, previously induced deep [objective response rate (ORR) 57.4%] durable [median duration of (DoR) 10.4 months] responses in adults with NTRK fusion-positive solid tumors from three phase I/II trials. This article expands prior reports additional patients longer follow-up. Patients Methods: locally advanced/metastatic ≥12 months' follow-up were included. Primary endpoints ORR DoR by blinded...
Genetic rearrangements of the tyrosine receptor kinase ROS proto-oncogene 1 (ROS1) are oncogenic drivers in non-small-cell lung cancer (NSCLC). We report results an updated integrated analysis three phase I or II clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2) ROS1 inhibitor, entrectinib, fusion-positive NSCLC.The efficacy-evaluable population included adults with locally advanced metastatic NSCLC without CNS metastases who received entrectinib ≥ 600 mg orally once per day....
Abstract Taselisib is a potent and selective tumor growth inhibitor through PI3K pathway suppression. Thirty-four patients with locally advanced or metastatic solid tumors were treated (phase I study, modified 3+3 dose escalation; 5 cohorts; 3–16 mg taselisib once-daily capsule). pharmacokinetics dose-proportional; mean half-life was 40 hours. Frequent dose-dependent, treatment-related adverse events included diarrhea, hyperglycemia, decreased appetite, nausea, rash, stomatitis, vomiting. At...
LBA1006 Background: Taselisib, a potent, selective PI3K inhibitor, has enhanced activity in PIK3CA-MUT BC cell lines and confirmed partial responses as single-agent or with FULV. We assessed taselisib + FULV pts ER-positive, HER2-negative, locally advanced MBC. Methods: SANDPIPER (NCT02340221) is double-blind, placebo (PBO)-controlled, randomized, phase III study. Postmenopausal disease recurrence progression during after an aromatase inhibitor were randomized 2:1 to receive (4 mg oral, qd)...
•Taselisib, a selective PI3K inhibitor, plus fulvestrant has clinical activity in PIK3CA-mutant, ER-positive breast cancer.•SANDPIPER (NCT02340221) assessed the efficacy of taselisib advanced cancer.•Taselisib had an expected safety profile, but with more discontinuations than placebo fulvestrant.•Taselisib versus significantly improved progression-free survival. BackgroundThe phase III SANDPIPER study (GDC-0032), potent, estrogen receptor-positive, HER2-negative, PIK3CA-mutant locally or...
Abstract Purpose: GDC-0084 is an oral, brain-penetrant small-molecule inhibitor of PI3K and mTOR. A first-in-human, phase I study was conducted in patients with recurrent high-grade glioma. Patients Methods: administered orally, once daily, to evaluate safety, pharmacokinetics (PK), activity. Fluorodeoxyglucose-PET (FDG-PET) performed measure metabolic responses. Results: Forty-seven heavily pretreated enrolled eight cohorts (2–65 mg). Dose-limiting toxicities included 1 case grade 2...
Abstract Purpose: Despite promising activity in hematopoietic malignancies, efficacy of the B-cell lymphoma 2 (BCL2) inhibitor venetoclax solid tumors is unknown. We report prespecified VERONICA primary results, a randomized phase II clinical trial evaluating and fulvestrant estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer, post–cyclin-dependent kinase (CDK) 4/6 progression. Patients Methods: Pre-/postmenopausal females ≥18 years were 1:1 to (800 mg orally daily) plus...
Abstract Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) has recently attracted attention as a potential therapeutic agent in the treatment of cancer. We assessed roles p53, TRAIL receptors, and cellular Fas-associated death domain–like interleukin-1β-converting enzyme inhibitory protein (c-FLIP) regulating cytotoxic effects recombinant (rTRAIL) alone combination with chemotherapy [5-fluorouracil (5-FU), oxaliplatin, irinotecan] panel colon cancer cell lines. Using clonogenic...
Abstract c-FLIP is an inhibitor of apoptosis mediated by the death receptors Fas, DR4, and DR5 expressed as long (c-FLIPL) short (c-FLIPS) splice forms. We found that small interfering RNA (siRNA)-mediated silencing induced spontaneous in a panel p53 wild-type, mutant, null colorectal cancer cell lines this was caspase-8 Fas-associated domain. Further analyses indicated involvement and/or Fas (but not DR4) regulating siRNA. Interestingly, these effects were dependent on activation or their...
Agents targeting the PI3K/mTOR signaling axis have shown promise in early-phase clinical trials and are currently being studied later stages of development multiple indications. Experience with other targeted agents suggests that responses may be short-lived because acquired resistance to therapy. Here, we report preclinical modeling a HER2-positive, PIK3CA mutant breast cancer cell line, KPL-4. We identified heretofore-unreported mechanism resistance, specifically high-level amplification...