Zachary A. Cooper
A5071770314- Melanoma and MAPK Pathways
- Cancer Immunotherapy and Biomarkers
- CAR-T cell therapy research
- Cancer Research and Treatments
- Immunotherapy and Immune Responses
- Cancer Mechanisms and Therapy
- PI3K/AKT/mTOR signaling in cancer
- Synthesis and biological activity
- Pancreatic and Hepatic Oncology Research
- Computational Drug Discovery Methods
- Salivary Gland Tumors Diagnosis and Treatment
- Neuroendocrine Tumor Research Advances
- Cutaneous Melanoma Detection and Management
- Peptidase Inhibition and Analysis
- Cytokine Signaling Pathways and Interactions
- Music Technology and Sound Studies
- HER2/EGFR in Cancer Research
- RNA regulation and disease
- Immune cells in cancer
- Adenosine and Purinergic Signaling
- Nanoplatforms for cancer theranostics
- Immune Cell Function and Interaction
- melanin and skin pigmentation
- Monoclonal and Polyclonal Antibodies Research
- Polyomavirus and related diseases
AstraZeneca (United States)
2017-2025
AstraZeneca (Japan)
2021-2024
The University of Texas MD Anderson Cancer Center
2013-2023
Center for Translational Molecular Medicine
2022
University of Colorado System
2021
University of Colorado Boulder
2021
AstraZeneca (Brazil)
2020
Novartis (Switzerland)
2016
Illumina (United States)
2016
GlaxoSmithKline (United Kingdom)
2016
Preclinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined oral and of melanoma patients undergoing anti-programmed cell death 1 protein (PD-1) immunotherapy (
Bacteria were first detected in human tumors more than 100 years ago, but the characterization of tumor microbiome has remained challenging because its low biomass. We undertook a comprehensive analysis microbiome, studying 1526 and their adjacent normal tissues across seven cancer types, including breast, lung, ovary, pancreas, melanoma, bone, brain tumors. found that each type distinct composition breast particularly rich diverse microbiome. The intratumor bacteria are mostly intracellular...
In model systems, bacteria present in human pancreatic tumors confer resistance to the anticancer drug gemcitabine.
T cell-mediated immunotherapies are promising cancer treatments. However, most patients still fail to respond these therapies. The molecular determinants of immune resistance poorly understood. We show that loss PTEN in tumor cells preclinical models melanoma inhibits killing and decreases T-cell trafficking into tumors. In patients, correlates with decreased infiltration at sites, reduced likelihood successful expansion from resected tumors, inferior outcomes PD-1 inhibitor therapy....
To evaluate the effects of BRAF inhibition on tumor microenvironment in patients with metastatic melanoma.Thirty-five biopsies were collected from 16 melanoma pretreatment (day 0) and at 10 to 14 days after initiation treatment either inhibitor alone (vemurafenib) or + MEK (dabrafenib trametinib) also taken time progression. Biopsies analyzed for antigens, T-cell markers, immunomodulatory cytokines.Treatment was associated an increased expression antigens increase CD8+ infiltrate. This a...
Immune checkpoint blockade represents a major breakthrough in cancer therapy; however, responses are not universal. Genomic and immune features pretreatment tumor biopsies have been reported to correlate with response patients melanoma other cancers, but robust biomarkers identified. We studied cohort of metastatic initially treated cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) (n = 53) followed by programmed death-1 (PD-1) at progression 46), analyzed signatures longitudinal tissue...
Immune checkpoint blockade produces clinical benefit in many patients. However, better biomarkers of response are still needed, and mechanisms resistance remain incompletely understood. To address this, we recently studied a cohort melanoma patients treated with sequential against cytotoxic T lymphocyte antigen-4 (CTLA-4) followed by programmed death receptor-1 (PD-1) identified immune markers resistance. Building on these studies, performed deep molecular profiling including cell receptor...
Most melanomas harbor oncogenic BRAF(V600) mutations, which constitutively activate the MAPK pathway. Although pathway inhibitors show clinical benefit in BRAF(V600)-mutant melanoma, it remains incompletely understood why 10% to 20% of patients fail respond. Here, we that RAF inhibitor-sensitive and inhibitor-resistant display distinct transcriptional profiles. Whereas most drug-sensitive cell lines patient biopsies showed high expression activity melanocytic lineage transcription factor...
Treatment of BRAF-mutant melanoma with combined dabrafenib and trametinib, which target RAF the downstream MAP-ERK kinase (MEK)1 MEK2 kinases, respectively, improves progression-free survival response rates compared monotherapy. Mechanisms clinical resistance to RAF/MEK inhibition are unknown. We performed whole-exome sequencing (WES) whole-transcriptome (RNA-seq) on pretreatment drug-resistant tumors from five patients acquired dabrafenib/trametinib. In three these patients, we identified...
Abstract Purpose: Treatment of melanoma patients with selective BRAF inhibitors results in objective clinical responses the majority BRAF-mutant tumors. However, resistance to these develops within a few months. In this study, we test hypothesis that inhibition combination adoptive T-cell transfer (ACT) will be more effective at inducing long-term regressions Experimental Design: BRAF-mutated human tumor cell lines transduced express gp100 and H-2Db allow recognition by gp100-specific pmel-1...
Abstract Purpose: In this study, we assessed the specific role of BRAF(V600E) signaling in modulating expression immune regulatory genes melanoma, addition to analyzing downstream induction suppression by primary human melanoma tumor-associated fibroblasts (TAF). Experimental Design: Primary melanocytes and cell lines were transduced express WT or V600E forms BRAF, followed gene analysis. The inhibitor vemurafenib was used confirm targets BRAF(V600E)-positive tumors from patients undergoing...
BRAF-targeted therapy results in objective responses the majority of patients; however, are short lived (∼6 months). In contrast, treatment with immune checkpoint inhibitors a lower response rate, but tend to be more durable. BRAF inhibition favorable tumor microenvironment patients, an increase CD8(+) T-cell infiltrate and decrease immunosuppressive cytokines. There is also increased expression immunomodulatory molecule PDL1, which may contribute resistance. On basis these findings, we...
Abstract BRAF mutations play a well-established role in melanomagenesis; however, without additional genetic alterations, tumor development is restricted by oncogene-induced senescence (OIS). Here, we show that the NF1 suppressor gene cooperate with melanomagenesis preventing OIS. In genetically engineered mouse model, Nf1 suppress Braf-induced senescence, promote melanocyte hyperproliferation, and enhance melanoma development. function deregulating both phosphoinositide 3-kinase...
An emerging concept in melanoma biology is that of dynamic, adaptive phenotype switching, where cells switch from a highly proliferative, poorly invasive to invasive, less proliferative one. This may hold significant implications not just for metastasis, but also therapy resistance. We demonstrate switching and subsequent resistance can be guided by changes expression receptors involved the noncanonical Wnt5A signaling pathway, ROR1 ROR2. ROR2 are inversely expressed melanomas negatively...
Durvalumab significantly improves overall survival for patients with unresectable stage III non-small-cell lung cancer and no progression after concurrent chemoradiotherapy (cCRT). Building upon that standard of care, COAST is a phase II study durvalumab alone or combined the anti-CD73 monoclonal antibody oleclumab anti-NKG2A monalizumab as consolidation therapy in this setting.Patients cancer, Eastern Cooperative Oncology Group performance status 0/1, cCRT were randomly assigned 1:1:1, ≤ 42...
Recently, the rationale for combining targeted therapy with immunotherapy has come to light, but our understanding of immune response during MAPK pathway inhibitor treatment is limited. We discovered that microenvironment can act as a source resistance pathway-targeted therapy, and moreover this becomes reinforced. In particular, we identified macrophage-derived TNFα crucial melanoma growth factor provides inhibitors through lineage transcription MITF (microphthalmia factor). Most...
<h3>Background</h3> Immune checkpoint blockade (ICB) promotes adaptive immunity and tumor regression in some cancer patients. However, patients with immunologically “cold” tumors, tumor-resident innate immune cell activation may be required to prime an response so exploit the full potential of ICB. Whilst Toll-like receptor (TLR) agonists have been used topically successfully treat superficial skin systemic TLR not well-tolerated. <h3>Methods</h3> The human cells TLR7 8 agonism was measured...