PhD Public Seminar: Oluwadara Coker, MS
When & Where
April 3
3:00 PM - 4:00 PM
(BSRB) GSBS Large Classroom, BSRB3.8371 6767 Bertner Ave, Houston TX 77030 (View in Google Map)
Contact
- Academic Affairs
- [email protected]
Event Description
Interrogating Therapeutic Resistance to KRASG12C- Based Therapies in Colorectal Cancer
Advisor: E. Scott Kopetz, MD, PhD
Colorectal cancer is the second leading cause of cancer-related deaths and the third most common cancer in the United States. Although KRAS is mutated in 50% of patients with metastatic CRC (mCRC), it has historically been a challenging therapeutic target. The recent approval of novel covalent inhibitors selective for KRASG12C mutation have entered the clinic, which has not only marked a major milestone in cancer drug discovery but has also intensified efforts to directly target other KRAS mutations that have also successfully entered the clinic. However, treatment-associated resistance mechanisms have long threatened to attenuate clinical benefit through either adaptive or acquired resistance. To better understand the impact of this mutation on this patient population, this dissertation has sought to characterize the clinical and molecular features using our MD Anderson Cancer Center cohort. To delineate the mechanisms of adaptive and acquired resistance, we have characterized our KRASG12C mCRC patient-derived xenograft models that were treated with KRASG12C targeted therapies and on-study paired biopsies from progressing patients. We examine the role of SHP2 as a mechanism of adaptive resistance and investigate the efficacy of a KRASG12C and SHP2 inhibitor combination in our in vivo models. We show that this combination has better efficacy than the well-established KRASG12C and EGFR inhibitor combination. Moreover, we identify YAP-TAZ-TEAD as a mechanism of acquired resistance in both our in vivo resistant models and in progressing patients. Finally, we interrogate novel YAP and pan-TEAD inhibitors for their clinical potential to overcome emergent resistance to KRASG12C and EGFR inhibitors for the goal of optimizing outcomes for patients with mCRC.
Advisory Committee:
Scott Kopetz, MD, PhD, Chair
Traver Hart, PhD
Lawrence Kwong, PhD
Wenyi Wang, PhD
John Paul Shen, MD
Anil Sood, MD
Attend via Zoom
Interrogating Therapeutic Resistance to KRASG12C- Based Therapies in Colorectal Cancer
Advisor: E. Scott Kopetz, MD, PhD
Colorectal cancer is the second leading cause of cancer-related deaths and the third most common cancer in the United States. Although KRAS is mutated in 50% of patients with metastatic CRC (mCRC), it has historically been a challenging therapeutic target. The recent approval of novel covalent inhibitors selective for KRASG12C mutation have entered the clinic, which has not only marked a major milestone in cancer drug discovery but has also intensified efforts to directly target other KRAS mutations that have also successfully entered the clinic. However, treatment-associated resistance mechanisms have long threatened to attenuate clinical benefit through either adaptive or acquired resistance. To better understand the impact of this mutation on this patient population, this dissertation has sought to characterize the clinical and molecular features using our MD Anderson Cancer Center cohort. To delineate the mechanisms of adaptive and acquired resistance, we have characterized our KRASG12C mCRC patient-derived xenograft models that were treated with KRASG12C targeted therapies and on-study paired biopsies from progressing patients. We examine the role of SHP2 as a mechanism of adaptive resistance and investigate the efficacy of a KRASG12C and SHP2 inhibitor combination in our in vivo models. We show that this combination has better efficacy than the well-established KRASG12C and EGFR inhibitor combination. Moreover, we identify YAP-TAZ-TEAD as a mechanism of acquired resistance in both our in vivo resistant models and in progressing patients. Finally, we interrogate novel YAP and pan-TEAD inhibitors for their clinical potential to overcome emergent resistance to KRASG12C and EGFR inhibitors for the goal of optimizing outcomes for patients with mCRC.
Advisory Committee:
Scott Kopetz, MD, PhD, Chair
Traver Hart, PhD
Lawrence Kwong, PhD
Wenyi Wang, PhD
John Paul Shen, MD
Anil Sood, MD
Attend via Zoom
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