Date: Monday, April 15, 2024

Time: 2:00 p.m.

Location: Virtual (https://gatech.zoom.us/j/97565579097)

Speakers/Abstracts:

David J. Shapiro, Ph.D., University of Illinois Urbana-Champaign Professor of Biochemistry

 We described the anticipatory Unfolded Protein Response (a-UPR) pathway used by estrogen, epidermal growth factor (EGF), and other agents that promote cell proliferation to prime cancer cells for future proliferation. We repurposed the tumor protective a-UPR through identification and optimization of the small molecule ErSO and its family of agents. ErSO acts by inducing lethal hyperactivation of the a-UPR. In orthotopic mouse xenografts whose proliferation is driven by wild type or therapy-resistant mutant estrogen receptor (ER), ErSO often induced complete regression without recurrence of large primary breast tumors and of most lung, bone and liver metastases, near complete regression of normally lethal brain metastases and complete destruction of patient derived organoids (PDOs) in 3-D culture. Moreover, ErSO often induced complete regression in multiple orthotopic xenograft models of primary and metastatic ovarian and uterine endometrial cancer. Using fresh ovarian cancer organoids immediately after removal from patients by paracentesis, ErSO destroyed the organoids from some patients with advanced stage III and stage IV disease. Surprisingly, ErSO induces complete, or near complete, regression of primary and metastatic human lung cancer in mice.

    Immunotherapy using checkpoint inhibitors has revolutionized cancer therapy but is usually ineffective against solid tumors. One way to potentially extend the reach of immunotherapy is to kill cancer cells by immune cell-activating necrosis. But necrosis lacked a pathway of action. Since ErSO kills cancer cells by inducing necrosis, we used genome-wide CRISPR screens with positive selection against ErSO and other methods to identify a multi-component pathway for necrosis used by ErSO and several other cancer therapies. Notably, medium from diverse cancer cells killed by ErSO-induced necrosis robustly activates human macrophage and induces their migration – potentially facilitating immunotherapy. These studies describe a pathway through the a-UPR, to a novel cell swelling and membrane rupture necrosis pathway that we are exploiting to target therapeutically challenging human cancers.

Susan N. Thomas, Ph.D., Georgia Tech Professor of Mechanical Engineering

My group develops enabling technologies to direct and/or model the cancer immunity cycle to augment immunotherapeutic outcomes. I will discuss our efforts to engineer new predictive modeling platforms for screening therapeutic cell products.

Jessica Stark, Ph.D., Massachusetts Institute of Technology Assistant Professor of Chemical Engineering

New paradigms to harness the immune system are necessary to address unmet needs in human health. Sugars called glycans coat the surface of every cell and, as a result, influence nearly every immunological process. However, our ability to identify which glycans control immune responses and to design therapies to target them remains limited. Our group is pioneering approaches to understand and engineer the roles of glycans in the immune system in order to 1) fill key knowledge gaps in immunobiology and 2) develop next-generation immunotherapies. In this talk, I will share examples of how we have used engineering approaches to begin to unlock the full potential of glycans for immunological discovery and immunotherapy.