Medical Pharmacology Commons^™

Acute Pressor Response To Psychosocial Stress Is Dependent On Endothelium‐Derived Endothelin‐1, Brandon M. Fox, Bryan K. Becker, Analia S. Loria, Kelly A. Hyndman, Chunhua Jin, Hannah Clark, Robin Johns, Masashi Yanagisawa, David M. Pollock, Jennifer S. Pollock

Pharmacology and Nutritional Sciences Faculty Publications

Background

Acute psychosocial stress provokes increases in circulating endothelin‐1 (ET‐1) levels in humans and animal models. However, key questions about the physiological function and cellular source of stress‐induced ET‐1 remain unanswered. We hypothesized that endothelium‐derived ET‐1 contributes to the acute pressor response to stress via activation of the endothelin A receptor.

Methods and Results

Adult male vascular endothelium‐specific ET‐1 knockout mice and control mice that were homozygous for the floxed allele were exposed to acute psychosocial stress in the form of cage switch stress (CSS), with blood pressure measured by telemetry. An acute pressor response was elicited by CSS in …

Binge Alcohol Exposure Causes Neurobehavioral Deficits And Gsk3Β Activation In The Hippocampus Of Adolescent Rats, Zhe Ji, Lin Yuan, Xiong Lu, Hanqing Ding, Jia Luo, Zun-Ji Ke

Pharmacology and Nutritional Sciences Faculty Publications

Heavy alcohol exposure causes profound damage to the adolescent brain, particularly the hippocampus, which underlie some behavioral deficits. However, the underlying molecular mechanisms remain inconclusive. The current study sought to determine whether binge alcohol exposure affects the hippocampus-related behaviors and key signaling proteins that may mediate alcohol neurotoxicity in adolescent rats. Alcohol exposure reduced the number of both NeuN-positive and doublecortin-positive cells in the hippocampus. Alcohol also induced neurodegeneration which was confirmed by ultrastructural analysis by electronic microscopy and was accompanied with the activation of microglia. Binge alcohol exposure impaired spatial learning and memory which was evaluated by the Morris …

Differential Impact Of Rb Status On E2f1 Reprogramming In Human Cancer., Christopher Mcnair, Kexin Xu, Amy C. Mandigo, Matteo Benelli, Benjamin E. Leiby, Daniel Rodrigues, Johan Lindberg, Henrik Gronberg, Mateus Crespo, Bram De Laere, Luc Dirix, Tapio Visakorpi, Fugen Li, Felix Y. Feng, Johann De Bono, Francesca Demichelis, Mark A. Rubin, Myles Brown, Karen E. Knudsen

Department of Cancer Biology Faculty Papers

The tumor suppressor protein retinoblastoma (RB) is mechanistically linked to suppression of transcription factor E2F1-mediated cell cycle regulation. For multiple tumor types, loss of RB function is associated with poor clinical outcome. RB action is abrogated either by direct depletion or through inactivation of RB function; however, the basis for this selectivity is unknown. Here, analysis of tumor samples and cell-free DNA from patients with advanced prostate cancer showed that direct RB loss was the preferred pathway of disruption in human disease. While RB loss was associated with lethal disease, RB-deficient tumors had no proliferative advantage and exhibited downstream effects …

Role Of Sex Chromosomes In Sexual Dimorphism Of Angii-Induced Abdominal Aortic Aneurysms, Yasir Alsiraj

Theses and Dissertations--Pharmacology and Nutritional Sciences

Abdominal aortic aneurysms (AAAs), a permanent dilation in the abdominal region of the aorta, is a highly sexually dimorphic disease. AAAs prevalence is ranging from 4-10 fold higher in males than females. Defining the mechanistic basis for reduced (in females) or increased (in males) AAA formation and progression may uncover potential therapeutic targets. The majority of studies examining sexual dimorphism focus on the role of sex hormones. However, genes residing on sex chromosomes, in addition to sex hormones, may contribute to sexual dimorphism of AAAs. For example, the X chromosome contains about 5% of the whole genome, but the role …

Neonatal Safety Information Reported To The Fda During Drug Development Studies., Debbie Avant, Gerri Baer, Jason N. Moore, Panli Zheng, Alfred Sorbello, Ron Ariagno, Lynne Yao, Gilbert J. Burckart, Jian Wang

Department of Pharmacology and Experimental Therapeutics Faculty Papers

BACKGROUND: Relatively few neonatal drug development studies have been conducted, but an increase is expected with the enactment of the Food and Drug Administration Safety and Innovation Act (FDASIA). Understanding the safety of drugs studied in neonates is complicated by the unique nature of the population and the level of illness. The objective of this study was to examine neonatal safety data submitted to the FDA in studies pursuant to the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) between 1998 and 2015.

METHODS: FDA databases were searched for BPCA and/or PREA studies that enrolled …

Subanesthetic Ketamine For Postoperative Analgesia: An Evidenced-Based Project, Jeremy Vance

Doctoral Projects

Roughly 100 million surgical procedures are performed in the United States (U.S.) each year and more than 80% of these patients experience acute postoperative pain. Pain costs the U.S. an estimated $560 to $635 billion annually and is a significant contributor to national rates of mortality, morbidity, and disability. Despite these findings, patients continue to receive suboptimal postoperative pain relief.

The adjunct administration of subanesthetic ketamine is opioid-sparing and can improve the effectiveness of a multimodal pain management approach. This project used an exploratory descriptive design to examine how an evidence-based presentation impacted the clinical practice of certified registered nurse …

Comparative Effectiveness And Safety Of Empagliflozin On Cardiovascular Mortality And Morbidity In Adults With Type 2 Diabetes, Wilbert S. Aronow, Tatyana Shamliyan

NYMC Faculty Publications

Background: Based on a single placebo-controlled randomized clinical trial, empagliflozin is licensed to reduce cardiovascular death in diabetes and comorbid cardiovascular disease. Methods: We examined the comparative effectiveness of empagliflozin on mortality and cardiovascular morbidity in type 2 diabetes. We conducted random-effects direct frequentist meta-analyses of aggregate data and appraised the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Our search in PubMed, EMBASE, the Cochrane Library, clinicaltrials.gov, and PharmaPendium up to May 2017 identified 11 meta-analyses, multiple publications, and unpublished data from 29 randomized controlled trials (RCTs). Results: Empagliflozin reduces all-cause mortality [relative …

Gucy2c Maintains Intestinal Lgr5+ Stem Cells By Opposing Er Stress, Crystal Kraft, Jeff A. Rappaport, Adam E. Snook, Amanda M. Pattison, John P. Lynch, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Long-lived multipotent stem cells (ISCs) at the base of intestinal crypts adjust their phenotypes to accommodate normal maintenance and post-injury regeneration of the epithelium. Their long life, lineage plasticity, and proliferative potential underlie the necessity for tight homeostatic regulation of the ISC compartment. In that context, the guanylate cyclase C (GUCY2C) receptor and its paracrine ligands regulate intestinal epithelial homeostasis, including proliferation, lineage commitment, and DNA damage repair. However, a role for this axis in maintaining ISCs remains unknown. Transgenic mice enabling analysis of ISCs (Lgr5-GFP) in the context of GUCY2C elimination (Gucy2c^-/-) were combined with immunodetection techniques …

Deletion Of The Nr4a Nuclear Receptor Nor1 In Hematopoietic Stem Cells Reduces Inflammation But Not Abdominal Aortic Aneurysm Formation, Hua Qing, Karrie L. Jones, Elizabeth B. Heywood, Hong Lu, Alan Daugherty, Dennis Bruemmer

Pharmacology and Nutritional Sciences Faculty Publications

Background: The NR4A3 orphan nuclear hormone receptor, NOR1, functions as a constitutively active transcription factor to regulate inflammation, proliferation, and cell survival during pathological vascular remodeling. Inflammatory processes represent key mechanisms leading to abdominal aortic aneurysm (AAA) formation. However, a role of NOR1 in AAA formation has not been investigated previously.

Methods: Inflammatory gene expression was analyzed in bone marrow-derived macrophages isolated from NOR1-deficient mice. Low-density lipoprotein receptor-deficient (LDLr^−/−) mice were irradiated and reconstituted with hematopoietic stem cells obtained from NOR1−/− or wild-type littermate mice. Animals were infused with angiotensin II and fed a diet enriched in saturated …

Finasteride As A Model For Personalized Medicine, Ion G. Motofei, David L. Rowland, Ioana Păunică, Octavian C. Tănăsescu, Petrişor Banu, Stana Păunică

Journal of Mind and Medical Sciences

The side effects of Finasteride are currently a subject of controversy. Some studies report minor or acceptable adverse effects, which decrease after a variable period of time so that they do not necessitate terminating Finasteride administration. However, several clinical and neuro-endocrine studies show that some adverse effects persist indefinitely in the form of post-Finasteride syndrome, even after the drug cessation. This paper presents a possible explanation for these inconsistent findings. First, the study design of either informing or not informing patients prior therapy about possible adverse effects can influence the incidence and magnitude of reported adverse effects. Second, structural and …

An Ethnobotanical Examination Of Traditional Medicine In Ngezi Forest Reserve, Tyler Tsang

Independent Study Project (ISP) Collection

Traditional medicine is an important aspect of the both the culture and health of communities worldwide. Ngezi Forest Reserve is a protected area on Pemba Island which is part of the Zanzibar Archipelago. This forest contains a wealth of botanical diversity which includes many species of medicinal plants. Traditional healers (waganga) use these medicinal plants to heal members of the community. Interviews and forest walks with these healers were supplemented by consultations with a botanist to determine medicinal value of the forest and the surrounding areas. In compiling information from 15 healers in the area, 98 species of medicinal plants …

The Heat-Stable Enterotoxin Receptor, Guanylyl Cyclase C, As A Pharmacological Target In Colorectal Cancer Immunotherapy: A Bench-To-Bedside Current Report., Trevor R. Baybutt, Allison A. Aka, Adam E. Snook

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Cancer immunotherapy is becoming a routine treatment modality in the oncology clinic, in spite of the fact that it is a relatively nascent field. The challenge in developing effective immunotherapeutics is the identification of target molecules that promote anti-tumor efficacy across the patient population while sparing healthy tissue from damaging autoimmunity. The intestinally restricted receptor guanylyl cyclase C (GUCY2C) is a target that has been investigated for the treatment of colorectal cancer and numerous animal, and clinical studies have demonstrated both efficacy and safety. Here, we describe the current state of GUCY2C-directed cancer immunotherapy and the future directions of this …

Hydroxyurea Lowers The Frequency Of Sickle Cell Vaso-Occlusive Crises, Corey S. Macrander

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med 1995;(332):1317-1322 doi: 10.1056/nejm199505183322001

Drug-Induced Causes Of Secondary Hypertension, Wilbert S. Aronow

NYMC Faculty Publications

No abstract provided.

Aligning Opioid Prescribing Pathways, Andrea Lai, Outpatient Pharmacy, Haley Pelletier, Suneela Nayak, Stephen Tyzik, Ruth Hanselman

MaineHealth Maine Medical Center

There is a drug epidemic sweeping the State of Maine and it continues to worsen each passing year. In 2017, the Maine legislature passed Public Law Chapter 488 to strengthen the controlled substance prescription monitoring program. An outpatient pharmacy, located in a large acute care hospital, created a performance improvement project to clarify opioid prescription and resolve any non-compliance with Chapter 488.

After a root cause analysis, several KPIs were established to include tracking the number of phone calls made by pharmacists to non-compliant providers to clarify scripts, provide one on one education and ultimately resolve non-compliance. Repeat offenders were …

Patient Fall Prevention, R9 West Cardiovascular, Cathy Palleschi, Suneela Nayak, Ruth Hanselman, Stephen Tyzik

MaineHealth Maine Medical Center

PATIENT FALL PREVENTION STRATEGIES IN AN ACUTE HOSPITAL

Every year in the United States, hundreds of thousands of patients fall resulting in injury. Injured patients often require prolonged hospital stays and a resultant increase in medical costs.

The purpose of this study was to identify the current state of fall prevention strategies on a hospital inpatient acute care cardiac unit. Through a root cause analysis, some deficiencies were identified and a process improvement plan was implemented.

Several positive outcomes were attained as a result of the countermeasures initiated. Patient falls per month and total waste in dollars saw a decline …

Communication Of Medication Side Effects In An Acute Care Hospital, Deb Bachand, Rachel Caiola, R6 Neurology Med-Surg Unit, Haley Pelletier, Brendan Lilley, Suneela Nayak, Ruth Hanselman, Stephen Tyzik

MaineHealth Maine Medical Center

COMMUNICATION OF MEDICATION SIDE EFFECTS IN AN ACUTE CARE HOSPITAL

Effective patient education of prescribed medication side effects improves patient safety and reduces overall risk. On an acute care hospital unit, nursing staff felt previous attempts at this education had been ineffective as demonstrated by their HCAHPs scores for communication about medications.

A root cause analysis demonstrated some flaws and several countermeasures were instituted. The goal of this KPI project was to attain a higher than national average for the specific HCAHPs score.

Post KPI inception, the unit’s HCAHPs data showed steady improvement. Within one month, the goal of an …

Brain Microvascular Injury And White Matter Disease Provoked By Diabetes-Associated Hyperamylinemia, Han Ly, Nirmal Verma, Fengen Wu, Miao Liu, Kathryn E. Saatman, Peter T. Nelson, John T. Slevin, Larry B. Goldstein, Geert Jan Biessels, Florin Despa

Pharmacology and Nutritional Sciences Faculty Publications

OBJECTIVE: The brain blood vessels of patients with type 2 diabetes and dementia have deposition of amylin, an amyloidogenic hormone cosecreted with insulin. It is not known whether vascular amylin deposition is a consequence or a trigger of vascular injury. We tested the hypothesis that the vascular amylin deposits cause endothelial dysfunction and microvascular injury and are modulated by amylin transport in the brain via plasma apolipoproteins.

METHODS: Rats overexpressing amyloidogenic (human) amylin in the pancreas (HIP rats) and amylin knockout (AKO) rats intravenously infused with aggregated amylin were used for in vivo phenotyping. We also carried out biochemical analyses …

Efficacy And Safety Of Sparsentan Compared With Irbesartan In Patients With Primary Focal Segmental Glomerulosclerosis: Randomized, Controlled Trial Design (Duet)., Radko Komers, Debbie S. Gipson, Peter Nelson, Sharon Adler, Tarak Srivastava, Vimal K. Derebail, Kevin E. Meyers, Pablo Pergola, Meghan E. Macnally, Jennifer L. Hunt, Alvin Shih, Howard Trachtman

Manuscripts, Articles, Book Chapters and Other Papers

Introduction: Primary focal segmental glomerulosclerosis (FSGS) is a leading cause of nephrotic syndrome and end-stage renal disease. There are no US Food and Drug Administration-approved therapies for FSGS, and treatment often fails to reduce proteinuria. Endothelin is an important factor in the pathophysiology of podocyte disorders, including FSGS. Sparsentan is a first-in-class, orally active, dual-acting angiotensin receptor blocker (ARB) and highly selective endothelin Type A receptor antagonist. This study is designed to evaluate whether sparsentan lowers proteinuria compared with an ARB alone and has a favorable safety profile in patients with FSGS.

Methods: DUET is a phase 2, randomized, active-control, …

Targeting Ledgf/P75 To Sensitize Chemoresistant Prostate Cancer Cells To Taxanes, Leslimar Rios-Colón

Loma Linda University Electronic Theses, Dissertations & Projects

Prostate cancer (PCa) is the second most diagnosed cancer in males. This disease disproportionately affects African American men, with a higher incidence and mortality compared to other ethnic/racial groups. An aging male population and the complexity of addressing the health disparities associated with this disease puts PCa into the spotlight due to its serious public health implications and the imminent fiscal challenge over the next decades. Chronic prostate inflammation resulting in activation of stress and prosurvival pathways contribute to disease progression and the development of chemoresistance. Lens epithelium-derived growth factor p75 (LEDGF/p75) is a stressresponse protein that promotes cellular survival …

Bioactivity Of Oral Linaclotide In Human Colorectum For Cancer Chemoprevention., David S. Weinberg, Jieru E. Lin, Nathan R. Foster, Gary Della'zanna, Asad Umar, Drew Seisler, Walter K. Kraft, David M. Kastenberg, Leo C. Katz, Paul J. Limburg, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Guanylate cyclase C (GUCY2C) is a tumor-suppressing receptor silenced by loss of expression of its luminocrine hormones guanylin and uroguanylin early in colorectal carcinogenesis. This observation suggests oral replacement with a GUCY2C agonist may be an effective targeted chemoprevention agent. Linaclotide is an FDA-approved oral GUCY2C agonist formulated for gastric release, inducing fluid secretion into the small bowel to treat chronic idiopathic constipation. The ability of oral linaclotide to induce a pharmacodynamic response in epithelial cells of the colorectum in humans remains undefined. Here, we demonstrate that administration of 0.87 mg of oral linaclotide daily for 7 days to healthy …

Tumor Necrosis Factor Inhibitors In Psoriatic Arthritis., Santhi Mantravadi, Alexis Ogdie, Walter K. Kraft

Department of Pharmacology and Experimental Therapeutics Faculty Papers

INTRODUCTION: Psoriatic arthritis (PsA) is a chronic inflammatory disease that can result in significant disability. With the emergence of tumor necrosis factor inhibitors (TNFi), therapeutic outcomes in PsA have improved substantially. The clinical efficacy and the inhibition of radiographic progression demonstrated by TNFi have transformed the management of PsA. However, there is still an unmet need for a subset of patients who do not respond adequately to TNFi. Areas covered: This review provides an overview of the pharmacokinetics of TNFi, the efficacy of TNFi in PsA, and the role of immunogenicity of TNFi in the treatment of PsA. In addition, …

The Nephrotoxicity Of Vancomycin., Edward J. Filippone, Walter K. Kraft, John L. Farber

Department of Medicine Faculty Papers

No abstract provided.

Sigma1 Targeting To Suppress Aberrant Androgen Receptor Signaling In Prostate Cancer., Jeffrey D. Thomas, Charles G. Longen, Halley M. Oyer, Nan Chen, Christina M. Maher, Joseph M. Salvino, Blase Kania, Kelsey N. Anderson, William F. Ostrander, Karen E. Knudsen, Felix J. Kim

Department of Cancer Biology Faculty Papers

Suppression of androgen receptor (AR) activity in prostate cancer by androgen depletion or direct AR antagonist treatment, although initially effective, leads to incurable castration-resistant prostate cancer (CRPC) via compensatory mechanisms including resurgence of AR and AR splice variant (ARV) signaling. Emerging evidence suggests that Sigma1 (also known as sigma-1 receptor) is a unique chaperone or scaffolding protein that contributes to cellular protein homeostasis. We reported previously that some Sigma1-selective small molecules can be used to pharmacologically modulate protein homeostasis pathways. We hypothesized that these Sigma1-mediated responses could be exploited to suppress AR protein levels and activity. Here we demonstrate that …

Targeting The Glucose Metabolism Of Myeloid-Derived Suppressor Cells (Mdscs) To Stimulate Cancer Immunity., Jaspreet Grewal

Electronic Theses and Dissertations

Myeloid derived suppressor cells (MDSCs) are a heterogeneous group of immature myeloid cells that are significantly increased in cancer patients and correlate with higher stage and poor prognosis. MDSCs negatively modulate anti-tumor immunity, suppress T cell activity, promote angiogenesis and increase the risk of metastasis. In this study, we report that monocytic-MDSCs (M-MDSCs) but polymorphonuclear-MDSCs (PMN-MDSCs) over-express 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatases 3 (PFKFB3), an important regulator of glycolysis. Furthermore in the melanoma model, M-MDSCs but not PMN-MDSCs suppressed T cell function which correlated with PFKFB3 over-expression and increased rate of glycolysis. PFKFB3 inhibition with the first-in-class small molecule inhibitor, PFK-158 reversed M-MDSC …

A Rare Case Of Vascular Ring And Coarctation Of The Aorta In Association With Charge Syndrome., Jonathan B. Wagner, Joshua Q. Knowlton, Peter Pastuszko, Sanket Shah

Manuscripts, Articles, Book Chapters and Other Papers

A male neonate presented with CHARGE syndrome, a multiorgan genetic disorder involving the Coloboma of the eyes, congenital Heart defects, nasal choanal Atresia, growth and development Retardation, Genitourinary disorders, and Ear anomalies and deafness. Moreover, he had a rare case of vascular ring-consisting of a right aortic arch with retroesophageal brachiocephalic artery-combined with coarctation of the mid-aortic arch. He underwent both vascular ring and aortic arch repair at our institution. To our knowledge, this is the 4th documented case of this exceedingly rare type of aortic arch anomaly combined with aortic arch obstruction. Moreover, it is the first confirmed case …

Topical Anaesthetics For Pain Control During Repair Of Dermal Laceration., Baraa O. Tayeb, Anthony Eidelman, Cristy L. Eidelman, Ewan D. Mcnicol, Daniel B. Carr

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Topical local anaesthetics provide effective analgesia for patients undergoing numerous superficial procedures, including repair of dermal lacerations. The need for cocaine in topical anaesthetic formulations has been questioned because of concern about adverse effects, thus novel preparations of cocaine-free anaesthetics have been developed. This review was originally published in 2011 and has been updated in 2017.

OBJECTIVES: To assess whether benefits of non-invasive topical anaesthetic application occur at the expense of decreased analgesic efficacy. To compare the efficacy of various single-component or multi-component topical anaesthetic agents for repair of dermal lacerations. To determine the clinical necessity for topical application …

Newborn Sequencing In Genomic Medicine And Public Health., Jonathan S. Berg, Pankaj B. Agrawal, Donald B. Bailey, Alan H. Beggs, Steven E. Brenner, Amy M. Brower, Julie A. Cakici, Ozge Ceyhan-Birsoy, Kee Chan, Flavia Chen, Robert J. Currier, Dmitry Dukhovny, Robert C. Green, Julie Harris-Wai, Ingrid A. Holm, Brenda Iglesias, Galen Joseph, Stephen F. Kingsmore, Barbara A. Koenig, Pui-Yan Kwok, John Lantos, J Steven Leeder, Megan A. Lewis, Amy L. Mcguire, Laura V. Milko, Sean D. Mooney, Richard B. Parad, Stacey Pereira, Josh E. Petrikin, Bradford C. Powell, Cynthia M. Powell, Jennifer M. Puck, Heidi L. Rehm, Neil Risch, Myra Roche, Joseph T. Shieh, Narayanan Veeraraghavan, Michael S. Watson, Laurel K. Willig, Timothy W. Yu, Tiina Urv, Anastasia L. Wise

Manuscripts, Articles, Book Chapters and Other Papers

The rapid development of genomic sequencing technologies has decreased the cost of genetic analysis to the extent that it seems plausible that genome-scale sequencing could have widespread availability in pediatric care. Genomic sequencing provides a powerful diagnostic modality for patients who manifest symptoms of monogenic disease and an opportunity to detect health conditions before their development. However, many technical, clinical, ethical, and societal challenges should be addressed before such technology is widely deployed in pediatric practice. This article provides an overview of the Newborn Sequencing in Genomic Medicine and Public Health Consortium, which is investigating the application of genome-scale sequencing …

Metronidazole Metabolism In Neonates And The Interplay Between Ontogeny And Genetic Variation., Laura A. Wang, Daniel Gonzalez, J Steven Leeder, Rachel F. Tyndale, Robin E. Pearce, Daniel K. Benjamin, Gregory L. Kearns, Michael Cohen-Wolkowiez, Best Pharmaceuticals For Children Act-Pediatric Trials Network Steering Committee

Manuscripts, Articles, Book Chapters and Other Papers

No abstract provided.

Inhibition Of The Integrin/Fak Signaling Axis And C-Myc Synergistically Disrupts Ovarian Cancer Malignancy, B. Xu, Jason R. Lefringhouse, Z. Liu, D. West, Lauren A. Baldwin, C. Ou, L. Chen, Dana L. Napier, Luksana Chaiswing, Lawrence D. Brewer, Daret K. St Clair, Olivier Thibault, John R. Van Nagell, Binhua P. Zhou, R. Drapkin, J.-A. Huang, M. L. Lu, Frederick R. Ueland, X. H. Yang

Pharmacology and Nutritional Sciences Faculty Publications

Integrins, a family of heterodimeric receptors for extracellular matrix, are promising therapeutic targets for ovarian cancer, particularly high-grade serous-type (HGSOC), as they drive tumor cell attachment, migration, proliferation and survival by activating focal adhesion kinase (FAK)-dependent signaling. Owing to the potential off-target effects of FAK inhibitors, disruption of the integrin signaling axis remains to be a challenge. Here, we tackled this barrier by screening for inhibitors being functionally cooperative with small-molecule VS-6063, a phase II FAK inhibitor. From this screening, JQ1, a potent inhibitor of Myc oncogenic network, emerged as the most robust collaborator. Treatment with a combination of VS-6063 …