Virtual Symposium: GPCRs in Oncology & Immuno-oncology
GPCRs represent the largest human membrane protein family and play a critical role in essential physiological and pathological processes.
With roughly a third of marketed drugs targeting GPCRs, the druggability of this family of receptors is unmatched. But despite this, their implication and drug discovery potential in oncology and immuno-oncology is relatively new.
Chaired by IRIC CEO Michel Bouvier, this virtual symposium showcased some of the latest discoveries and techniques leveraging the potential of GPCRs in these crucial fields.
Leading experts shared findings from world-class academic and private research on GPCRs in oncology and immuno-oncology.
And as well as taking part in live Q&As after each presentation, the attendees had the chance to discuss topics and network with speakers near the end of the symposium.
To relive the Symposium and catch up on the presentations, head up to this link: https://www.youtube.com/watch?v=gr0WirF2NPI&t=251s
9:00 am to 9:15 am (EDT) Opening and intro by Michel Bouvier (CEO, IRIC)
9:15 am to 10:00 am (EDT) Talk 1, Martine J. Smit
10:00 am to 10:45 am (EDT) Talk 2, Xavier Leroy
11:00 am to 11:45 am (EDT) Talk 3, Sébastien Carréno
11:45 am to 12:30 pm (EDT) Talk 4, J. Silvio Gutkind
*Each talk will be followed by a 15-minute Q&A
12:30 pm to 12:45 pm (EDT) Closing remarks by Michel Bouvier (CEO, IRIC)
12:45 pm to 13:15 pm (EDT) Live-hosted Q&A. Attendees may engage and ask questions to the speaker directly.
Room 1: Martine J. Smit (Speaker) – Shane Wright (Chair)
Room 2: Sébastien Carréno (Speaker) – Maria Majellaro (Chair)
Room 3: Xavier Leroy (Speaker) – Guilhem Dugast (Chair)
Room 4: Silvio Gutkind (Speaker) – Alexander Hauser (Chair)
TALK 1: Nanobodies Modulating Oncogenic Signaling Networks Activated by Human and Viral Chemokine Receptors
9:15 am to 10:00 am (EDT)
Speaker: Martine J. Smit
Professor of Target and Systems Biochemistry
Faculty of Science, Vrije Universiteit Amsterdam
Chemokine receptors play a key role in the immune system, directing leukocytes to lymphoid tissues and sites of inflammation. In addition, chemokines and their receptors are involved in organogenesis and angiogenesis, as well as in tumorigenesis.
Herpes viruses have hijacked the chemokine receptor system through expression of viral G protein-coupled receptors (GPCRs), altering cellular signaling after viral infection.
We have shown that several viral GPCRs, including the CMV-encoded chemokine receptors, signal in a constitutive manner, rewire proliferative and pro-inflammatory signaling pathways.
Interestingly, expression of these receptors has been detected in tumor samples of glioblastoma patients and its expression induced tumor formation in orthotopic xenograft model systems.
Nanobodies, single domain antibody fragments, targeting these human and viral chemokine receptors were shown to effectively attenuate proliferative signaling in vitro and tumor progression in vivo.
Formatted (monovalent/multivalent constructs) nanobodies, incorporating different modalities (fluorophores, photosensitizers, effector function) serve as important pharmacological tools to target and dissect the role of (viral) chemokine receptors in cancer.
TALK 2: Monoclonal Antibodies Targeting GPCRs in Immuno-Oncology
10:00 am to 10:45 am (EDT)
Speaker: Xavier Leroy
Chief Scientific Officer, Domain Therapeutics
TALK 3: Studying the Role of the Thromboxane A2 Receptor During Metastasis of Triple Negative Breast Cancers
11:00 am to 11:45 am (EDT)
Speaker: Sébastien Carréno
Principal Investigator, Cellular Mechanisms of Morphogenesis Research Unit, IRIC
Metastasis is responsible for 90% of cancer deaths. Metastatic cells acquire the ability to invade the surrounding stroma, to modulate the microenvironment and colonize distant organs by undergoing genetic modifications. But to acquire metastatic abilities, tumor cells also engage in a complex crosstalk with cells of the stroma.
The physiology of metastatic cells is still poorly understood, for instance, the mechanisms that prompt cancer cells to disseminate are still a mystery.
In collaboration with Michel Bouvier’s laboratory, we discovered a novel signalling pathway that can contribute to metastatic progression.
We found that the Thromboxane A2 receptor (TBXA2R) – a G-protein coupled receptor (GPCR) – activates Ezrin, Radixin and Moesin (ERMs), a family of proteins playing important roles in metastasis.
ERMs regulate cell morphogenesis by linking actin filaments and microtubules to the plasma membrane. Importantly, ERMs participate in the aggressiveness of numerous cancers by promoting cell invasion and metastasis. We developed biosensors that can individually monitor Ezrin, Radixin and Moesin activation in living cells. Using these, we identified the signalling pathway that TBXA2R engages to promote cell motility through activation of ERMs in a model of triple negative breast cancer.
TALK 4: Mutational Landscape of G Proteins and GPCRs in Cancer: New Multimodal Precision Cancer Therapies
11:45 am to 12:30 pm (EDT)
Speaker: J. Silvio Gutkind
Distinguished Professor and Chair, Department of Pharmacology, School of Medicine, and Associate Director of Basic Science, Moores Cancer Center, University of California San Diego (UCSD), La Jolla, California, USA
Member, National Academy of Medicine
GPCRs are widely dysregulated in cancer, and yet largely underexploited in oncology.
GPCRs and G proteins are mutated in >25% of human neoplastic diseases, and aberrantly expressed in multiple human malignancies. Some of the most prevalent cancers deploy GPCR oncocrine networks to promote tumor growth, metastasize, and evade immunosurveillance.
In turn, targeting GPCRs and their regulated signaling circuitry can be exploited for the development of novel precision cancer treatments and to increase the response to immunotherapies.
Specifically, we will focus on uveal melanoma (UM) – the second most common melanoma subtype – which is caused by GNAQ oncogenes encoding constitutively active mutants of Gαq and Gα11 G protein α subunits.
The use of a computational platform to identify synthetic lethal gene interactions with GNAQ revealed that the tyrosine kinase FAK is a druggable target in UM. By the use of unbiased genetic screens, we recently uncovered that horizontal inhibition of FAK and the adaptive activation of ERK results in rapid regression of UM liver metastatic lesions. This finding provided the foundation for the first signal transduction-based multimodal precision therapy in metastatic UM.
Computational approaches to investigate how GPCRs modulation can be exploited to increase the response to immunotherapies will be also discussed.
Thank you to the event sponsor, Domain Therapeutics