A5007792747- Estrogen and related hormone effects
- Advanced Breast Cancer Therapies
- HER2/EGFR in Cancer Research
- Cancer Treatment and Pharmacology
- DNA Repair Mechanisms
- Cancer Genomics and Diagnostics
- DNA and Nucleic Acid Chemistry
- Acute Myeloid Leukemia Research
- PARP inhibition in cancer therapy
- Cancer-related Molecular Pathways
- PI3K/AKT/mTOR signaling in cancer
- Radiation Effects and Dosimetry
- Chronic Myeloid Leukemia Treatments
- Chronic Lymphocytic Leukemia Research
- Lung Cancer Treatments and Mutations
- Protein Tyrosine Phosphatases
- Protein Degradation and Inhibitors
- Radiopharmaceutical Chemistry and Applications
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Chromatin Remodeling and Cancer
- RNA and protein synthesis mechanisms
- Neurofibromatosis and Schwannoma Cases
- Colorectal Cancer Treatments and Studies
- Protein Kinase Regulation and GTPase Signaling
- Occupational and environmental lung diseases
University of California, San Francisco
2004-2023
Sarah Cannon
2018-2019
Dana-Farber Cancer Institute
2018-2019
Tennessee Oncology
2018-2019
Institut Català d'Oncologia
2018
Hospital Clínico Universitario de Valencia
2018
Clinica Universidad de Navarra
2018
Centro de Investigación Biomédica en Red de Cáncer
2018
UCSF Helen Diller Family Comprehensive Cancer Center
2010-2017
Pediatrics and Genetics
2009-2012
Abstract Purpose: This first-in-human phase I trial assessed the safety, tolerability, and preliminary antitumor activity of apitolisib (GDC-0980), a dual inhibitor class PI3K, mTOR kinases. Experimental Design: Once-daily oral was administered to patients with solid tumors for days 1 21 or 28 28-day cycles. Pharmacokinetic pharmacodynamic parameters were assessed. Results: Overall, 120 treated at doses between 2 70 mg. The commonest ≥G3 toxicities related recommended dose (RP2D) 40 mg once...
Children with neurofibromatosis type 1 (NF1) are predisposed to juvenile myelomonocytic leukemia (JMML), an aggressive myeloproliferative neoplasm (MPN) that is refractory conventional chemotherapy. Conditional inactivation of the Nf1 tumor suppressor in hematopoietic cells mice causes a progressive MPN accurately models JMML and chronic (CMML). We characterized effects loss on immature populations investigated treatment MEK inhibitor PD0325901 (hereafter called 901). Somatic resulted marked...
Inhibiting the Raf/MEK/ERK pathway reverses harmful effects of oncogenic Kras on hematopoietic differentiation, suggesting a strategy for treating myeloproliferative neoplasms.
BACKGROUND The current single‐arm, open‐label trial was designed to evaluate the activity of apitolisib (GDC‐0980), a dual phosphoinositide 3‐kinase/mammalian target rapamycin (PI3K/mTOR) inhibitor, in patients with advanced endometrial cancer (EC). METHODS Patients recurrent or persistent EC who were treated 1 2 prior lines chemotherapy but no PI3K/mTOR inhibitor received oral at dose 40 mg daily during 28‐day cycles until disease progression intolerable toxicity occurred. type I/II...
Purpose: Chk1 inhibition potentiates DNA-damaging chemotherapy by overriding cell-cycle arrest and genome repair. This phase I study evaluated the inhibitor GDC-0425 given in combination with gemcitabine to patients advanced solid tumors.Experimental Design: Patients received alone for a 1-week lead-in followed 21-day cycles of plus GDC-0425. Gemcitabine was initially administered at 750 mg/m2 (Arm A), then increased 1,000 B), on days 1 8 3 + dose escalation establish maximum tolerated...
Checkpoint kinase 1 (Chk1) inhibition following chemotherapy-elicited DNA damage overrides cell cycle arrest and induces mitotic catastrophe death. GDC-0575 is a highly-selective oral small-molecule Chk1 inhibitor that results in tumor shrinkage growth delay xenograft models. We evaluated the safety, tolerability, pharmacokinetic properties of alone combination with gemcitabine. Antitumor activity pathway modulation were assessed.In this phase I open-label study, dose escalation stage,...
3020 Background: The PI3K-AKT-mTOR signaling pathway is deregulated in a wide variety of cancers. GDC-0980 potent, selective, oral inhibitor class I PI3K and mTOR kinase with vitro IC50 4.8 nM for p110α/p85α apparent Ki 17.3 human mTOR. demonstrates broad activity xenograft cancer models (breast, ovarian, lung, prostate). Methods: A phase dose-escalation study (PIM4604g) using 3+3 design was initiated patients (pts) solid tumors. given on Day 1, followed by 1 wk washout to single-dose...
Abstract The RASopathies, one of the largest groups multiple congenital anomaly syndromes known, are caused by germline mutations in various genes encoding components Ras/mitogen‐activated protein kinase (MAPK) pathway. RASopathies have many overlapping characteristics, including craniofacial manifestations, cardiac malformations, cutaneous, musculoskeletal, gastrointestinal, and ocular abnormalities, neurocognitive impairment, hypotonia, an increased risk developing cancer. Costello...
Abstract Background: Modulation of estrogen activity and/or synthesis is the mainstay therapeutic strategy in treatment ER+ BC. However, despite effectiveness available endocrine therapies, many patients ultimately relapse or develop resistance to these agents via estrogen-dependent and estrogen-independent mechanisms, including mutations ESR1 affecting ER ligand binding domain that drive ER-dependent transcription proliferation absence estrogen. antagonists are efficacious against...
577 Background: Modulation of ER activity and/or estrogen synthesis is the mainstay therapeutic strategy in ER+ BC treatment. Giredestrant a highly potent, nonsteroidal oral selective degrader (SERD) that achieves robust occupancy and effective regardless ESR1 mutation status. The first short-term preoperative WOO study (NCT03916744) giredestrant ER+/HER2– operable was designed for dose selection, while providing an early readout PD as measured by traditional immunohistochemistry (IHC)...
Abstract Purpose: GDC-0927 is a novel, potent, nonsteroidal, orally bioavailable, selective estrogen receptor (ER) degrader that induces tumor regression in ER+ breast cancer xenograft models. Patients and Methods: This phase I dose-escalation multicenter study enrolled postmenopausal women with ER+/HER2− metastatic to determine the safety, pharmacokinetics, recommended II dose of GDC-0927. Pharmacodynamics was assessed [18F]-fluoroestradiol (FES) PET scans. Results: Forty-two patients...
5513 Background: Treatment options for patients with recurrent or persistent endometrial cancer (EC) are limited. The PI3K/AKT/mTOR pathway has been implicated in the pathogenesis of EC. This single arm, open-label trial was designed to evaluate activity GDC-0980, a dual PI3K/mTOR inhibitor, advanced NCT01455493. Methods: Patients EC treated 1 2 prior lines chemotherapy but no inhibitor received oral GDC-0980 40 mg daily on 28-day cycle until progression intolerable toxicity. Type I/II...
Abstract Background: Checkpoint kinase 1 (Chk1) acts at S and G2/M checkpoints to allow time for high-fidelity DNA replication repair before cell cycle progression. Chk1 inhibition converts a transient genotoxic insult from chemotherapy into cytotoxic event by overriding arrest, allowing cells mitosis with damage. GDC-0425 is an oral, selective inhibitor. enhances gemcitabine (gem) efficacy in tumor xenograft models. Greater chemopotentiation observed cancer lines lacking p53 activity....
Abstract Background: The PI3K-AKT-mTOR signaling pathway is deregulated in a wide variety of cancers. GDC-0980 potent, selective, oral inhibitor class I PI3K and mTOR kinase demonstrating broad activity xenograft cancer models (breast, ovarian, lung, prostate). Methods: A Phase dose escalation study using 3+3 design has been initiated patients (pts) with advanced solid tumors or non-Hodgkin's lymphoma. administered QW. objectives are to determine the dose-limiting toxicities (DLTs) maximum...