J. Silvio Gutkind

J. Silvio Gutkind
University of California, San Diego | UCSD · Department of Pharmacology

Ph.D.

About

780
Publications
83,359
Reads
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56,514
Citations
Introduction
I am a basic scientist with a passion for exploiting the emerging information on dysregulated signaling circuitries and individual genomic and molecular alterations to develop new precision therapies to prevent and treat cancer. My laboratory has focused on the study of growth-promoting signal transduction pathways, the nature of the dysregulated signaling networks in cancer with emphasis on head and neck cancer and ocular melanoma (OM), and on the use of genomic, proteomic, and system biology approaches to study cancer progression. Based on our clinical trial targeting mTOR in oral cancer, we are now also exploring the effectiveness of PI3K/mTOR inhibitors for oral cancer prevention and treatment, and new multimodal precision immunotherapies for oral cancer and other malignancies.
Additional affiliations
September 2015 - present
University of California, San Diego
Position
  • Managing Director
December 1987 - December 1988
National Cancer Institute (USA)
Position
  • PostDoc Position
December 1987 - August 2015
National Institutes of Health
Position
  • Branch Chief

Publications

Publications (780)
Article
With the continued promise of immunotherapy as an avenue for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer risk screening and treatment strategies. Using genotypes from over 8,000 European individuals in The Cancer Genome Atlas and 137 heritable tumor immune...
Article
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, resulting in over 14,600 deaths each year in the United States alone. HNSCC is associated with human papillomavirus (HPV) infection, tobacco use, and abusive alcohol intake. Without truly effective targeted therapies, surgery and radiotherapy represent the prim...
Article
Natural killer (NK) cells are a key effector in antitumor immunity. However, tumors often acquire resistance programs to escape NK cell-mediated immunosurveillance. Identifying targetable vulnerabilities that reinvigorate NK cell-driven antitumor immunity can enable new therapeutic strategies to improve NK cell-mediated anti-tumor activity. Previou...
Article
Full-text available
Background Understanding the intricate signaling network involved in triple-negative breast cancer (TNBC) represents a challenge for developing novel therapeutic approaches. Here, we aim to provide novel mechanistic insights on the function of the S100A8/A9-RAGE system in TNBC. Methods TNM plot analyzer, Kaplan-Meier plotter, Meta-analysis, GEPIA2...
Article
Full-text available
In this study we show that protein language models can encode structural and functional information of GPCR sequences that can be used to predict their signaling and functional repertoire. We used the ESM1b protein embeddings as features and the binding information known from publicly available studies to develop PRECOGx, a machine learning predict...
Article
Full-text available
Head and neck squamous cell carcinoma (HNSCC) represents a highly prevalent and deadly malignancy worldwide. The prognosis for locoregionally advanced HNSCC has not appreciably improved over the past 30 years despite advances in surgical, radiation, and targeted therapies and less than 20% of HNSCC patients respond to recently approved immune check...
Article
Purpose/Objective(s) PD-1 inhibition (PD1i) has demonstrated no benefit for locally advanced HNSCC, and emerging neoadjuvant PD1i window of opportunity yield promising but limited responses. Our preclinical work demonstrates that ablating tumor draining lymphatics compromises the response to immune-oncology (IO) therapy. In concert, a recently comp...
Article
Purpose/Objective(s) Objective response rates to PD-1 blockade in human papillomavirus (HPV) mediated Head and Neck Squamous cell carcinoma (HNSCC) are low and resistance mechanisms are unclear. HPV oncogenes are known to modulate immune responses; however, the role that they play in limiting responses to PD-1 blockade is poorly understood. Here we...
Article
Full-text available
Extensive knowledge has been gained on the transcription network controlled by ERα, however, the mechanism underlying ESR1 (encoding ERα) expression is less understood. We recently discovered that the Hippo pathway is required for the proper expression of ESR1. YAP/TAZ are transcription coactivators that are phosphorylated and inhibited by the Hipp...
Preprint
Immune checkpoint inhibition (ICI) with anti-CTLA-4 and anti-PD-1 has revolutionized oncology; however, response rates remain limited in most cancer types, highlighting the need for more effective immune oncology (IO) treatment strategies. Paradoxically, head and neck squamous cell carcinoma (HNSCC), which bears a mutational burden and immune infil...
Article
Full-text available
Lymphangiogenesis is an essential physiological process but also a determining factor in vascular-related pathological conditions. Angiopoietin-2 (Ang2) plays an important role in lymphatic vascular development and function and its upregulation has been reported in several vascular-related diseases, including cancer. Given the established role of t...
Article
Head and neck squamous cell carcinoma (HNSCC) ranks 6th in cancer incidence worldwide and has a five-year survival rate of only 63%. Immunotherapies - principally immune checkpoint inhibitors (ICI), such as anti-PD-1 and anti-CTLA-4 antibodies that restore endogenous antitumor T-cell immunity - offer the greatest promise for HNSCC treatment. Anti-P...
Preprint
Despite the promise of immune checkpoint inhibition (ICI), therapeutic responses remain limited. This raises the possibility that standard of care treatments delivered in concert may compromise the tumor response. To address this, we employed tobacco-signature HNSCC murine models in which we mapped tumor-draining lymphatics and developed models for...
Preprint
Full-text available
Head and neck squamous cell carcinoma (HNSCC) ranks 6th in cancer incidence worldwide and has a five-year survival rate of only 63%. Immunotherapies ,principally immune checkpoint inhibitors (ICI), such as anti-PD-1 and anti-CTLA-4 antibodies that restore endogenous antitumor T-cell immunity, offer the greatest promise for HNSCC treatment. Anti-PD-...
Article
Full-text available
The Hippo pathway is frequently dysregulated in cancer, leading to the unrestrained activity of its downstream targets, YAP/TAZ, and aberrant tumor growth. However, the precise mechanisms leading to YAP/TAZ activation in most cancers is still poorly understood. Analysis of large tissue collections revealed YAP activation in most head and neck squam...
Article
Background Despite the proven efficacy of immune checkpoint inhibitor (ICI) therapy in the recurrent/metastatic setting for head and neck squamous cell carcinoma (HNSCC), clinical trials of ICI combined with curative-intent therapies have yielded equivocal results [1–4]. Collectively, this highlights gaps in our understanding of rational immune onc...
Preprint
Full-text available
Targeted therapy is effective in many tumor types including lung cancer, the leading cause of cancer mortality. Paradigm defining examples are targeted therapies directed against non-small cell lung cancer (NSCLC) subtypes with oncogenic alterations in EGFR, ALK and KRAS. The success of targeted therapy is limited by drug-tolerant tumor cells which...
Article
Full-text available
A major goal of cancer research is to understand how mutations distributed across diverse genes affect common cellular systems, including multiprotein complexes and assemblies. Two challenges—how to comprehensively map such systems and how to identify which are under mutational selection—have hindered this understanding. Accordingly, we created a c...
Article
We outline a framework for elucidating tumor genetic complexity through multidimensional protein-protein interaction maps and apply it to enhancing our understanding of head and neck squamous cell carcinoma. This network uncovers 771 interactions from cancer and noncancerous cell states, including WT and mutant protein isoforms. Prioritization of c...
Article
Many of the fundamental concepts of signal transduction and kinase activity are attributed to the discovery and crystallization of cAMP-dependent protein kinase, or protein kinase A. PKA is one of the best-studied kinases in human biology, with emphasis in biochemistry and biophysics, all the way to metabolism, hormone action, and gene expression r...
Article
Epithelial plasticity, or epithelial-to-mesenchymal transition (EMT), is a well-recognized form of cellular plasticity, which endows tumor cells with invasive properties and alters their sensitivity to various agents, thus representing a major challenge to cancer therapy. It is increasingly accepted that carcinoma cells exist along a continuum of h...
Article
Full-text available
Background: The aberrant activation of the PI3K/mTOR signaling circuitry is one of the most frequently dysregulated signaling events in head and neck squamous cell carcinoma (HNSCC). Here, we conducted a single-arm, open label phase IIa clinical trial (NCT02581137) in individuals with oral premalignant lesions (OPL) to explore the potential of met...
Conference Paper
p>Head and neck squamous cell carcinoma (HNSCC) ranks 6th in cancer incidence worldwide and has a five-year survival rate of only 63%. Despite advances in curative-intent therapies over the past three decades, rates of recurrence exceed 50% and long-term toxicities remain unacceptably morbid. Immunotherapies - principally immune checkpoint inhibito...
Conference Paper
p>Developing effective therapies to intervene in the tumor immune evasion process is a challenge further complicated by interindividual variability in tumor-host immunological interactions. Germline variation is a major component of interindividual variability usually studied by large-scale genome-wide association studies (GWAS) in the context of d...
Article
TPS9588 Background: Despite successful treatment of primary uveal melanomas (UM), up to 50% of patients subsequently develop systemic metastasis, with the liver involved in up to 90% of patients. Currently there is no US FDA-approved treatment for metastatic uveal melanoma (MUM). Activating mutations in genes encoding alpha subunits of the heterotr...
Article
Full-text available
Immune checkpoint blockade (ICB) therapy has revolutionized head and neck squamous cell carcinoma (HNSCC) treatment, but <20% of patients achieve durable responses. Persistent activation of the PI3K/AKT/mTOR signaling circuitry represents a key oncogenic driver in HNSCC; however, the potential immunosuppressive effects of PI3K/AKT/mTOR inhibitors m...
Preprint
With the continued promise of immunotherapy as an avenue for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer risk screening and treatment strategies. Using genotypes from over 8,000 European individuals in The Cancer Genome Atlas (TCGA) and 137 heritable tumor...
Article
Full-text available
Targeted therapies for gastrointestinal stromal tumor (GIST) are modestly effective, but GIST cannot be cured with single agent tyrosine kinase inhibitors. In this study, we sought to identify new therapeutic targets in GIST by investigating the tumor microenvironment. Here, we identified a paracrine signaling network by which cancer-associated fib...
Article
Senescent cells produce chronic inflammation that contributes to the diseases and debilities of aging. How this process is orchestrated in epithelial cells, the origin of human carcinomas, is poorly understood. We used human normal oral keratinocytes (NOKs) to elucidate senescence programs in a prototype primary mucosal epithelial cell that senesce...
Article
Purpose: Uveal melanoma (UM) is the most common eye cancer in adults. Approximately 50% of UM patients develop metastatic UM (mUM) in the liver, even after successful treatment of the primary lesions. mUM is refractory to current chemo- and immune-therapies, and most mUM patients die within a year. UM is characterized by gain-of-function mutations...
Article
Full-text available
Breast cancer represents the most common diagnosed malignancy and the main leading cause of tumor-related death among women worldwide. Therefore, several efforts have been made in order to identify valuable molecular biomarkers for the prognosis and prediction of therapeutic responses in breast tumor patients. In this context, emerging discoveries...
Article
Full-text available
The DNA demethylating agent 5-aza-2′-deoxycytidine (DAC, decitabine) has anti-cancer therapeutic potential, but its clinical efficacy is hindered by DNA damage-related side effects and its use in solid tumours is debated. Here we describe how paracetamol augments the effects of DAC on cancer cell proliferation and differentiation, without enhancing...
Article
G protein coupled receptors (GPCRs) and heterotrimeric G proteins play central roles in a diverse array of cellular processes. As such, dysregulation of GPCRs and their coupled heterotrimeric G proteins can dramatically alter the signalling landscape and functional state of a cell. Consistent with their fundamental physiological functions, GPCRs an...
Article
Background Oncologically-sound standard of care therapy often indicates ablation of draining lymphatic basins to eradicate repositories of metastatic disease. However, emerging cancer immunotherapies often necessitate intact secondary lymphoid organs to achieve maximum effect. Therefore, multimodal immune-oncology (IO) therapeutic approaches introd...
Article
A low-cost microfluidic microarray capable of lysing cells and quantifying proteins released after lysis was designed and 3D-printed. The array lyses cells on-chip in lysis buffer augmented with a 2s pulse of a sonic cell disruptor. Detection of desmoglein 3 (DSG3), a metastatic biomarker for head and neck squamous cell carcinoma (HNSCC), along wit...
Article
Full-text available
Gα proteins promote dynamic adjustments of cell shape directed by actin cytoskeleton reorganization via their respective RhoGEF effectors. For example, Gα13 binding to the RGS-homology (RH) domains of several RH-RhoGEFs allosterically activates these proteins, causing them to expose their catalytic DH/PH regions, which triggers downstream signals....
Article
Full-text available
The dominant paradigm for HPV carcinogenesis includes integration into the host genome followed by expression of E6 and E7 (E6/E7). We explored an alternative carcinogenic pathway characterized by episomal E2, E4, and E5 (E2/E4/E5) expression. Half of HPV positive cervical and pharyngeal cancers comprised a subtype with increase in expression of E2...
Conference Paper
In prior studies, we have shown that persistent activation of the PI3K/mTOR signaling circuitry is the most frequently dysregulated signaling pathway in HNSCC (>80% of all HPV- and HPV+ cases), and that mTOR inhibitors (mTORi) exert potent antitumor activity in multiple experimental HNSCC model systems and in a recent Phase 2 clinical trial. In thi...
Conference Paper
p>Uveal melanoma (UM) is characterized by gain-of-function mutations in GNAQ or GNA11 , encoding Gα proteins from the Gq/11 family. UM is the most common eye malignancy in adults. Approximately 50% of UM patients develop liver metastasis (mUM) within 5-10 years after diagnosis, independently of the successful treatment of the primary lesions. mUM i...
Conference Paper
Natural killer (NK) cells play a key role in tumor immune surveillance by their ability to recognize and kill both hematological and solid tumor cells. NK cell-based immunotherapy is emerging as a powerful treatment against certain malignancies. However, intrinsic and extrinsic mechanisms can lead tumor cells to develop resistance mechanisms to esc...
Conference Paper
The Cancer Genome Atlas and similar projects have now analyzed over 10,000 tumor genomes, providing a catalog of the gene mutations, copy number variants and other genetic alterations that are present cancer. In many cases though, it remains unclear which are the key driver mutations or dependencies in a given cancer and how these influence pathoge...
Article
In this issue of Cell Stem Cell, Jia et al. (2020) • Jia L. • Zhang W. • Wang C.-Y. BMI1 Inhibition Eliminates Residual Cancer Stem Cells after PD1 Blockade and Activates Antitumor Immunity to Prevent Metastasis and Relapse. Cell Stem Cell. 2020; 27 ( this issue) : 238-253 • Google Scholar identify residual cancer stem cells (CSCs) as a mechani...
Conference Paper
Dysregulation of the Hippo signaling pathway and the consequent YAP1 activation is a frequent event in human malignancies, yet the underlying molecular mechanisms are still poorly understood. In prior studies we have focused on uveal melanoma, the most frequent eye malignancy in adults that is caused by constitutively active mutations in the GNAQ o...
Conference Paper
YAP overactivation is an essential molecular event for cancer initiation and growth of most solid tumors, but pharmacologic targeting of the YAP or Hippo pathway has been proven to be challenging. In this regard, YAP activity is also required for stem and progenitor cell maintenance and function in multiple tissues, and as such, YAP is necessary fo...
Article
Full-text available
Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase (FT). FT catalyzes the post-translational attachment of farnesyl groups to signaling proteins that are required for localization to cell membranes. Although all RAS isoforms are FT substrates, only HRAS is exclusively dependent upon farnesylation, raising the possibility t...
Article
Among the three nonmuscle myosin 2 (NM2) paralogs, NM 2A and 2B, but not 2C, are detected in endothelial cells. To study the role of NM2 in vascular formation we ablate NM2 in endothelial cells in mice. Ablating NM2A, but not NM2B, results in reduced blood vessel coverage and increased vascular branching in the developing mouse skin and coronary va...
Article
Full-text available
Among the three nonmuscle myosin 2 (NM2) paralogs, NM 2A and 2B, but not 2C, are detected in endothelial cells. To study the role of NM2 in vascular formation we ablate NM2 in endothelial cells in mice. Ablating NM2A, but not NM2B, results in reduced blood vessel coverage and increased vascular branching in the developing mouse skin and coronary va...
Article
Full-text available
GPCRs are increasingly recognized to initiate signaling via heterotrimeric G proteins as they move through the endocytic network, but little is known about how relevant G protein effectors are localized. Here we report selective trafficking of adenylyl cyclase type 9 (AC9) from the plasma membrane to endosomes while adenylyl cyclase type 1 (AC1) re...
Article
Full-text available
GPCRs are increasingly recognized to initiate signaling via heterotrimeric G proteins as they move through the endocytic network, but little is known about how relevant G protein effectors are localized. Here we report selective trafficking of adenylyl cyclase type 9 (AC9) from the plasma membrane to endosomes while adenylyl cyclase type 1 (AC1) re...
Article
Full-text available
GPCRs are increasingly recognized to initiate signaling via heterotrimeric G proteins as they move through the endocytic network, but little is known about how relevant G protein effectors are localized. Here we report selective trafficking of adenylyl cyclase type 9 (AC9) from the plasma membrane to endosomes while adenylyl cyclase type 1 (AC1) re...
Conference Paper
Natural killer (NK) cells play a key role in tumor immune surveillance by their ability to recognize and kill both hematologic and solid tumor cells. NK cell-based immunotherapy is emerging as a powerful treatment against certain malignancies. However, intrinsic and extrinsic mechanisms can lead tumor cells to develop resistance mechanisms to escap...
Article
Full-text available
Alternative mRNA splicing increases protein diversity, and alternative splicing events (ASEs) drive oncogenesis in multiple tumor types. However, the driving alterations that underlie the broad dysregulation of ASEs are incompletely defined. Using head and neck squamous cell carcinoma (HNSCC) as a model, we hypothesized that the genomic alteration...
Article
Full-text available
Background: Patients with metastatic uveal melanoma (MUM) in the liver usually die within 1 year. The development of new treatments for MUM has been limited by the lack of diverse MUM cell lines and appropriate animal models. We previously reported that orthotopic xenograft mouse models established by direct injection of MUM cells into the liver w...
Article
e15658 Background: HRAS is an important driver oncogene in HNSCC and other squamous cell carcinomas (SCCs). HRAS mutations are observed in 6-10% of HNSCC cases and appear to define a unique subset of HNSCC associated with wild-type TP53, co-mutations in caspase 8 and a characteristic methylation pattern. RAS proteins undergo several posttranslation...
Article
Cetuximab, a monoclonal antibody targeting EGFR, is a standard of care for the treatment for locally advanced or metastatic head and neck squamous cell carcinoma (HNSCC). However, despite overexpression of EGFR in over 90% of HNSCC lesions, most HNSCC patients fail to respond to cetuximab treatment. In addition, there are no available biomarkers to...
Article
Full-text available
Prostate cancer (PCa) innervation contributes to the progression of PCa. However, the precise impact of innervation on PCa cells is still poorly understood. By focusing on muscarinic receptors, which are activated by the nerve-derived neurotransmitter acetylcholine, we show that muscarinic receptors 1 and 3 (m1 and m3) are highly expressed in PCa c...
Preprint
Full-text available
GPCRs are increasingly recognized to initiate signaling via heterotrimeric G proteins as they move through the endocytic network, but little is known about how relevant G protein effectors are localized. Here we report dynamic trafficking of adenylyl cyclase type 9 (AC9) from the plasma membrane to endosomes, while adenylyl cyclase type 1 (AC1) rem...
Article
Full-text available
Triple-negative breast cancer (TNBC) is an aggressive breast tumor subtype that currently lacks targeted treatment options. The role played by the insulin-like growth factor-1 (IGF-1) and its cognate receptor IGF-1R in TNBC has been reported. Nevertheless, the molecular mechanisms by which the IGF-1/IGF-1R system may contribute to TNBC progression...