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Targeting the Endocannabinoid System for Treatment of Human Diseases

WEBINAR

Only

Targeting the Endocannabinoid System for Treatment of Human Diseases

Wednesday, January 27, 2021, 11:00 AM - 5:15 PM EST

WEBINAR

Presented By

The New York Academy of Sciences

 

The endocannabinoid system (ECS) maintains homeostasis in the body by regulating physiologic processes including neurotransmission, mood, energy balance, immune responses, and wound healing. Functions of the ECS are mediated by two cannabinoid receptors, Type 1 and 2 (CB1 and CB2). This meeting will focus on the understanding of the physiology and pharmacology of the peripheral endocannabinoid system. The goal is to illuminate the roles of CB1 and CB2 receptors with regard to possible discovery and development of entirely new classes of drugs for the treatment of inflammatory, immune, and fibrotic disorders.

Event Image Credit: Corbus Pharmaceuticals

Registration

Member
$30
Nonmember Academia, Faculty, etc.
$65
Nonmember Corporate, Other
$85
Nonmember Not for Profit
$65
Nonmember Student, Undergrad, Grad, Fellow
$45
Member Student, Post-Doc, Fellow
$15
Earlybird Registration:
0
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Deadline:
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Scientific Organizing Committee

Allyn Howlett
Allyn Howlett, PhD

Wake Forest School of Medicine

Barbara White
Barbara White, MD

Corbus Pharmaceuticals

George Zavoico, PhD
George Zavoico, PhD

Cue Biopharma

Sonya Dougal, PhD
Sonya Dougal, PhD

The New York Academy of Sciences

Barbara Knappmeyer, PhD
Barbara Knappmeyer, PhD

The New York Academy of Sciences

Speakers

Derek W. Gilroy
Derek W. Gilroy, PhD

University College London

Andrea Hohmann, PhD
Andrea Hohmann, PhD

Indiana University Bloomington

Allyn Howlett
Allyn C. Howlett, PhD

Wake Forest School of Medicine

Aron H. Lichtman, PhD
Aron H. Lichtman, PhD

Virginia Commonwealth University

George Kunos, MD, PhD
George Kunos, MD, PhD

National Institute on Alcohol Abuse and Alcoholism

Kenneth Mackie
Kenneth Mackie, MD

Indiana University

Kathryn Nichol, PhD
Kathryn Nichol, PhD

Greenwich Biosciences

Barbara White
Barbara White, MD

Corbus Pharmaceuticals

Wednesday

January 27, 2021

11:00 AM

Opening Remarks

Speaker

The New York Academy of Sciences
11:05 AM

Biology and Pharmacology of Endocannabinoid System - Overview

Speaker

Allyn Howlett, PhD
Wake Forest School of Medicine

Session 1: CB1

11:40 AM

Regulation of Appetite and Addictive Behavior by the Peripheral Endocannabinoid System

Speaker

George Kunos, MD, PhD
National Institute on Alcohol Abuse and Alcoholism
12:10 PM

TBD

Speaker

Kathryn Nichol, PhD
Greenwich Biosciences
12:40 PM

TBD

Speaker

Aron H. Lichtman, Ph.D.
Virginia Commonwealth University
1:10 PM

Lunch Break

1:40 PM

Cannabinoids for Weight Loss: A Twisted Tale

Speaker

Kenneth Mackie, MD
Indiana University

Cannabis stimulates consumption of calorically dense, nutritionally poor food (AKA “the munchies”). Surprisingly, most epidemiological studies have found an association between chronic cannabis use and reduced body weight, central obesity, and risk for type II diabetes, despite a poor diet. To understand the metabolically protective effects of cannabis, we have investigated THC’s interactions with

GPR119, a nutrient-sensing G protein coupled receptor, found in pancreas and the gut. GPR119 activation by partially digested lipids increases insulin secretion and sensitivity, preserves beta cell mass, and enhances incretin secretion. GPR119 signaling was assessed in HEK293 cells stably expressing GPR119 and GluTag cells endogenously expressing GPR119. Wildtype C57BL/6J and GPR119 knockout mice were made obese by a high fat diet (HFD). Mice were treated with vehicle or various drugs and their weights recorded.

1) THC and its metabolites activated GPR119 in a functionally-selective fashion, 2) THC and its metabolites increased GLP-1 secretion from GluTag cells, 3) THC, administered intraperitoneally or orally, induced reversible weight loss in obese wildtype, but not GPR119 KO mice, 4) THC administered to adolescent mice, concurrently with a HFD, attenuated HFD-induced weight gain.

These results suggest that sustained use of cannabis might activate GPR119, leading to weight loss (or attenuated weight gain), increased incretin secretion and an overall improvement in metabolic health.

Coauthors: Amey Dhopeshwarkar, Parhesh Kumar, and Jim Wager-Miller, Indiana University.

2:10 PM

Cannabidiol (CBD) Inhibits Cancer Survival Through Upregulating the Endoplasmic Reticulum (ER) Stress Response

Speaker

Andrea Watters
NYIT College of Osteopathic Medicine

Cannabis has resurfaced as a natural treatment for medical conditions such as AIDS wasting syndrome, chemotherapy-related nausea and vomiting and epilepsy syndromes. The bioactive molecules in the Cannabis sativa plant include exogenous cannabinoids, such as CBD and Δ9-tetrahydrocanabinol (THC). CBD has been shown to have anti-proliferative and pro-apoptotic effects as well as preventing invasion and metastasis of various cancers. However, the mechanism by which CBD exerts its effects is not fully understood. Here, we investigated CBD’s effects on the long-term viability and mechanisms of cell death in a variety of cancer cell lines including osteosarcoma, cervical adenocarcinoma, metastatic breast cancer, large cell lung carcinoma and malignant melanoma. The IC50 of each cancer cell line varied from 2.45-8.47µM. Apoptosis as a mechanism of cell death was confirmed by the presence of PARP cleavage. The IC50 was about 3-fold higher for the normal skin fibroblasts compared to melanoma cells, suggesting a therapeutic window in which CBD preferentially kills skin cancer cells. RNA-Seq analysis suggested that heightened ER stress response in CBD-treated melanoma cells was the likely cause of cell death. This was further confirmed by the upregulation of the apoptosis-inducing ER stress protein CHOP. In the future, we plan to further validate the mechanism by which CBD kills cancer cells as well as develop a CBD cream and test its efficacy on preventing and/or treating skin cancers.

2:20 PM

Panel Discussion 1

Speakers

Moderator: Allyn Howlett, PhD
Wake Forest School of Medicine)
George Kunos, MD, PhD
National Institute on Alcohol Abuse and Alcoholism
Kathryn Nichol, PhD
Greenwich Biosciences
Aron H. Lichtman, PhD
Virginia Commonwealth University
Kenneth Mackie, MD
Indiana University
2:45 PM

Break

Session 2: CB2

2:55 PM

New Insights into the Resolution of Acute Inflammation in Humans Provided by Lenabasum, a Synthetic Analogue of delta -8- tetrahydrocannabinol (THC)-11-oic Acid

Speaker

Derek Gilroy, PhD
University College London

The current therapeutic strategy for treating chronic inflammatory diseases is based largely upon inhibiting the factors that drive acute inflammation and include nonsteroidal anti-inflammatory drug, steroids and biologics. Although these medicines ameliorate some disease symptoms, they do not bring about a ‘cure’. Thus, there is a significant need to identify more effective and safer therapeutics to treat chronic inflammatory diseases. One emerging approach is to harness the body’s own inflammatory resolution process for therapeutic gain. Lenabasum is a synthetic analogue of delta -8- tetrahydrocannabinol (THC)-11-oic acid that in pre-clinical models of experimental inflammation exerts potent anti-inflammatory actions with minimal CNS cannabimimetic activity. Using a model of acute inflammation driven by i.d. UV-killed E. coli in healthy humans we found that Lenabasum exerted a potent anti-inflammatory effect equivalent to that of prednisolone in terms of inhibiting neutrophil infiltration, the hallmark of acute inflammation. These effects arose from the inhibition of the neutrophil chemoattractant LTB4, while the inhibition of anti-phagocytic prostanoids (PGE2,) resulted in enhanced clearance of inflammatory stimulus from the injected site. One striking observation that we made was the Lenabasum may trigger the synthesis of endogenous gases synonymous with proresolution of inflammation. In this presentation we will provide an update on this are of research and present a novel pathway for the resolution of diseases driven by chronic inflammation in humans.

Coauthors: James Glanville and Madhur P. Motwani, University College London; and Barbara White, Corbus Pharmaceuticals.

3:25 PM

Medical Marijuana and the Endocannabinoid System: Therapeutic Potential for Treating Neuropathic Pain

Speaker

Andrea Hohmann, PhD
Indiana University Bloomington
3:55 PM

Therapeutic Potential of Targeting Cannabinoid Type 1 and Type 2 Receptors

Speaker

Barbara White, MD
Corbus Pharmaceuticals
4:25 PM

Break

4:35 PM

CRB-317, a Selective Cannabinoid Receptor Type 2 (CB2) Agonist, Inhibits NLRP3 Inflammasome Activation, Cytokine Production, and Has Activity in a Model of Gouty Arthritis

Speaker

Ping Zhang, PhD, MD
Corbus Pharmaceuticals

Background/Hypothesis: CB2 is expressed on activated immune cells and promotes resolution of innate immune responses. Gouty arthritis is the most prevalent inflammatory arthritis in men in the US and is caused by an innate immune response to monosodium urate crystals (MSU). MSU in joints stimulate cytokine production through TLR2/4-mediated NFKbeta activation and activate NLRP3 inflammasomes to release IL-1beta and IL-18, causing joint inflammation. The hypothesis of this research was that CRB-317, a selective CB2 agonist, would inhibit components of an innate immune response involved in the pathogenesis of gouty arthritis and show efficacy in an animal model of the disease. Methods/ Results: CRB-317 reduced production of TNFalpha, IL-6, MCP-1, and IL-23 by human PBMC stimulated through TLR4 with LPS, effects that were inhibited by a CB2 antagonist. CRB-317 induced a dose-dependent decline in caspase 1, IL-1beta, and IL-18 in a model of NLRP3 inflammasome activation via CB2 receptor in LPS/ATP-stimulated monocyte-derived macrophages. In a MSU rat model of acute gouty arthritis, oral administration of 5 and 10 mg/kg CRB-317 prior to (Day -1), at the time of intraarticular MSU injection and for 4 additional doses over 48 hours reduced knee swelling by 40% and 51%, respectively, compared to vehicle control. Conclusions: Selective CB2 agonists such as CRB-317 may have therapeutic potential in human diseases caused by an innate immune response, such as gouty arthritis.

4:45 PM

Panel Discussion 2

Speakers

Moderator: George Kunos, MD, PhD
National Institute on Alcohol Abuse and Alcoholism
Derek Gilroy, PhD
University College London
Andrea Hohmann, PhD
Indiana University Bloomington
Barbara White, MD
Corbus Pharmaceuticals
5:10 PM

Closing Remarks

5:15 PM

Adjourn

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