A5068500323- Cancer Immunotherapy and Biomarkers
- Renal cell carcinoma treatment
- Cancer, Hypoxia, and Metabolism
- Cancer Research and Treatments
- CAR-T cell therapy research
- Cancer Genomics and Diagnostics
- RNA modifications and cancer
- Renal and related cancers
- Ferroptosis and cancer prognosis
- Extracellular vesicles in disease
- Ocular Surface and Contact Lens
- Advanced Breast Cancer Therapies
- Immune cells in cancer
- Virus-based gene therapy research
- Monoclonal and Polyclonal Antibodies Research
- Epigenetics and DNA Methylation
- Corneal surgery and disorders
- Allergic Rhinitis and Sensitization
- Pancreatic and Hepatic Oncology Research
- Corneal Surgery and Treatments
- Nanoplatforms for cancer theranostics
- Immunotherapy and Immune Responses
- CRISPR and Genetic Engineering
- Glaucoma and retinal disorders
- Phagocytosis and Immune Regulation
The University of Texas Southwestern Medical Center
2008-2024
North Carolina State University
2024
Incyte (United States)
2017-2023
Southwestern Medical Center
2007-2022
University of California, Berkeley
2012
Blocking the activity of programmed cell death protein 1 (PD-1) inhibitory receptor with therapeutic antibodies against either ligand (PD-L1) or PD-1 itself has proven to be an effective treatment modality for multiple cancers. Contrasting antibodies, small molecules could demonstrate increased tissue penetration, distinct pharmacology, and potentially enhanced antitumor activity. Here, we describe identification characterization INCB086550, a novel, oral, small-molecule PD-L1 inhibitor. In...
By leveraging tumorgraft (patient-derived xenograft) RNA-sequencing data, we developed an empirical approach, DisHet, to dissect the tumor microenvironment (eTME). We found that 65% of previously defined immune signature genes are not abundantly expressed in renal cell carcinoma (RCC) and identified 610 novel immune/stromal transcripts. Using eTME, genomics, pathology, medical record data involving >1,000 patients, established inflamed pan-RCC subtype (IS) enriched for regulatory T cells,...
Targeting metabolic vulnerabilities has been proposed as a therapeutic strategy in renal cell carcinoma (RCC). Here, we analyzed the metabolism of patient-derived xenografts (tumorgrafts) from diverse subtypes RCC. Tumorgrafts VHL -mutant clear RCC (ccRCC) retained features human ccRCC and engaged oxidative reductive glutamine metabolism. Genetic silencing isocitrate dehydrogenase-1 or dehydrogenase-2 impaired labeling tricarboxylic acid (TCA) cycle intermediates vivo suppressed growth...
Background Preclinical evaluation of drugs targeting the human immune system has posed challenges for oncology researchers. Since commercial introduction humanized mice, antitumor efficacy and pharmacodynamic studies can now be performed with cancer cells within mice bearing components a system. However, development characterization these models is necessary to understand which model may best suited different agents. Methods We characterized A375, A549, Caki-1, H1299, H1975, HCC827, HCT116,...
Metastasis is the principal cause of cancer related deaths. Tumor invasion essential for metastatic spread. However, determinants are poorly understood. We addressed this knowledge gap by leveraging a unique attribute kidney cancer. Renal tumors invade into large vessels forming tumor thrombi (TT) that migrate extending sometimes heart. Over decade, we prospectively enrolled 83 ethnically-diverse patients undergoing surgical resection grossly invasive at UT Southwestern Kidney Cancer...
TYRO3, AXL, and MERTK constitute the TAM family of receptor tyrosine kinases, which play important roles in tumor growth, survival, cell adhesion, as well innate immunity, phagocytosis, immune-suppressive activity. Therefore, targeting both AXL kinases may directly impact growth relieve immunosuppression. We describe here discovery INCB081776, a potent selective dual inhibitor that is currently phase 1 clinical trials. In cellular assays, INCB081776 effectively blocked autophosphorylation or...
mTORC1 is aberrantly activated in renal cell carcinoma (RCC) and targeted by rapalogs. As for other therapies, rapalogs clinical utility limited the development of resistance. Resistance often results from target mutation, but mTOR mutations are rarely found RCC. humans, prolonged rapalog treatment RCC tumorgrafts (TGs) led to Unexpectedly, explants resistant tumors became sensitive both culture subsequent transplants mice. Notably, resistance developed despite persistent inhibition tumor...
Abstract A large body of evidence suggests that corneal allograft rejection is mediated by a type 1 Th cell response and deviation toward 2 immunity favors graft survival. However, clinical observations indicate patients with severe ocular allergies have increased risk rejection. We used mouse model atopic conjunctivitis to evaluate the effects Th2 immune on survival possible mechanisms Our results reveal following novel findings: 1) promotes systemic responses donor alloantigens; 2)...
Several studies suggest that a significant number of corneal allografts undergo rejection in the absence CD4 T cells. This study examined role cell-independent mechanisms allograft rejection.BALB/c were transplanted to C57BL/6 beige nude mice received either CD8 or cells from knockout (KO) had rejected BALB/c allografts. Immune effector functions KO assessed using delayed-type hypersensitivity assays and Annexin V apoptosis respectively. RESULTS.: Both rejector mediated following adoptive...
Corneal allografts transplanted into hosts with allergic conjunctivitis experience an increased incidence and swifter tempo of immune rejection compared to corneal nonallergic hosts. Previous findings suggested that risk for was not a local effect produced by inflamed eye, but due perturbation the systemic responses alloantigens on allograft. We tested hypothesis another disease, airway hyperreactivity (AHR), would also increase allograft rejection. Induction AHR either ovalbumin (OVA) or...
Abstract Allergic conjunctivitis (AC) and airway hyperreactivity exacerbate corneal allograft rejection. Because AC are allergic diseases of mucosal tissues, we determined whether an disease a nonmucosal tissue would affect rejection Th2 cells alone accounted for accelerated graft in mice. Hosts sensitized cutaneously with short ragweed pollen developed cutaneous immediate hypersensitivity but rejected allografts at the same tempo incidence as naive immune deviation induced keyhole limpet...
Immune checkpoint inhibitors (ICI) targeting the programmed cell death protein 1 and its ligand (PD-1/PD-L1) have transformed treatment paradigm for metastatic renal carcinoma (RCC). However, response rates to ICIs as single agents or in combination vary widely predictive biomarkers are lacking. Possibly related heterogeneity dynamic nature of PD-L1 expression, tissue-based methods shown limited value. Immuno-positron emission tomography (immunoPET) may enable noninvasive, comprehensive,...
Abstract Purpose: HIF2α is a key driver of kidney cancer. Using belzutifan analogue (PT2399), we previously showed in tumorgrafts (TG) that ∼50% clear cell renal carcinomas (ccRCC) are dependent. However, prolonged treatment induced resistance mutations, which also identified humans. Here, evaluated tumor-directed, systemically delivered, siRNA drug (siHIF2) active against wild-type and resistant-mutant HIF2α. Experimental Design: our credentialed TG platform, performed pharmacokinetic...
Abstract Tyro-3, Axl, and Mer constitute the TAM family of receptor tyrosine kinases (RTKs), which are amplified, translocated, or over-expressed in numerous types human cancer. These RTKs play important roles tumor growth, survival, cell adhesion migration as well drug resistance. In addition, it has been shown that both AXL MER critical regulators innate immunity, phagocytosis, immune-suppressive activity. Therefore targeting may not only impact survival malignant progression neoplastic...
A growing body of empirical research finds that mothers and caretakers experience significant workplace penalties, including negative evaluations, lower pay, reduced prospects for promotion. Can law reduce these penalties caretakers? We present recent theoretical developments uncover the social psychological mechanisms producing disadvantages. then discuss our theory results an experimental laboratory study show how laws prohibiting discrimination against workers who take family leave can...
Abstract The majority of clear cell renal carcinoma (ccRCC) have deficiency in the gene encoding von Hippel Landau (VHL) protein, as a result DNA copy loss, non-sense mutations, and epigenetic silencing. Deficiency VHL its E3 ligase activity results stabilization transcription factors hypoxia-inducible factor (HIF)-1α HIF-2α. In ccRCC, HIF-2α has been proposed to function an oncogenic driver, depletion tumor cells inhibition growth. We previously described identification potent selective...
Supplementary Figure from Characterization of INCB086550: A Potent and Novel Small-Molecule PD-L1 Inhibitor
Abstract In the tumor microenvironment, dying cells release ATP which gets converted to AMP by CD39. is subsequently immunosuppressive adenosine extracellular 5'-nucleotidase CD73. CD73 linked cell surface a GPI-anchor and can be released into plasma as soluble order lower levels reverse activity of in an antibody was researched discovered that antagonizes function. INCA00186 humanized monoclonal binds inhibits human cynomolgus with sub-nanomolar affinity, enzymatic manner non-competitive...
Abstract Normally induced by hypoxia, hypoxia-inducible factor 2 alpha (HIF2a) is arguably the most important driver of kidney cancer. HIF2a constitutively activated following von Hippel-Lindau (VHL) gene inactivation, which signature event common type cancer, clear cell renal carcinoma (ccRCC). functions as a heterodimeric transcription in partnership with constitutive HIF1b subunit and regulates program expression that promotes proliferation, stemness, angiogenesis. While had escaped drug...
Abstract In the tumor microenvironment, ATP released by dying cells is converted to adenosine, a well-established potent suppressor of immune cell activity. The suppressive function extracellular adenosine mediated through two G-protein coupled receptors known as A2A and A2B. Both are expressed on many types cells. While A2B has traditionally been considered less relevance compared due lower affinity its ligand recent evidence suggests specific role in myeloid cancer. To determine whether...