MS Public Seminar: MARC PINA
When & Where
October 14
2:00 PM - 3:00 PM
UT MD Anderson Cancer Center, 3SCR3.3202A (View in Google Map)
Contact
- Joy A. Lademora
- 713-500-9872
- [email protected]
Event Description
SIK2 Inhibitor GRN-300 Enhances Sensitivity to Paclitaxel Treatment in Triple-Negative Breast Cancer
Marc Anthony Pina, BS (Advisor: Robert Bast, MD)
Breast cancer is one of the most frequently diagnosed cancers worldwide, with approximately 15% classified as Triple-Negative Breast Cancer (TNBC). TNBC lacks expression of estrogen (ER) and progesterone (PR), and does not overexpress HER-2, leaving patients without effective targeted therapies. As a result, treatment primarily relies on chemotherapy, most commonly paclitaxel, a taxane that stabilizes microtubules, disrupts chromosome separation and induces apoptosis. However, TNBCs are an aggressive cancer subtype, and patients often will develop resistance after a few rounds of chemotherapy. This study addresses a critical unmet need for more effective TNBC therapies by targeting Salt-Inducible Kinase 2 (SIK2), which is overexpressed in 88% of TNBC specimens compared to normal breast tissue. We hypothesize that SIK2 inhibition could enhance paclitaxel efficacy and overcome resistance. In collaboration with Arrien Pharmaceuticals and Greenfire Biologics, we developed ARN-3261/GRN-300, a novel orally administered SIK2 inhibitor and evaluated its ability to sensitize TNBC cells to paclitaxel in vitro and in vivo. GRN-300 demonstrated strong synergy with paclitaxel in 8 of 9 TNBC cell lines tested, as indicated by combination indices. In xenograft models, the combination produced tumor growth inhibition and improved survival compared to either agent alone. Mechanistic studies showed that GRN-300 disrupts the APC/C pathway by downregulating key mitotic regulators, including CDC27, CDK1, and PLK1, resulting in enhanced G2/M arrest and apoptosis. Notably, GRN-300 retained activity in paclitaxel-resistant TNBC cell lines, suggesting the potential to overcome acquired resistance. Together, these findings establish GRN-300 as a promising first-in-class SIK2 inhibitor that augments paclitaxel efficacy through complementary disruption of mitotic pathways, providing strong preclinical rationale for clinical development in TNBC.
Advisory Committee:
- Robert Bast, MD, Chair
- Chandra Bartholomeusz, PhD
- Bisrat Debeb, DVM, PhD
- Catherine Denicourt, PhD
- Zhen Lu, MD
SIK2 Inhibitor GRN-300 Enhances Sensitivity to Paclitaxel Treatment in Triple-Negative Breast Cancer
Marc Anthony Pina, BS (Advisor: Robert Bast, MD)
Breast cancer is one of the most frequently diagnosed cancers worldwide, with approximately 15% classified as Triple-Negative Breast Cancer (TNBC). TNBC lacks expression of estrogen (ER) and progesterone (PR), and does not overexpress HER-2, leaving patients without effective targeted therapies. As a result, treatment primarily relies on chemotherapy, most commonly paclitaxel, a taxane that stabilizes microtubules, disrupts chromosome separation and induces apoptosis. However, TNBCs are an aggressive cancer subtype, and patients often will develop resistance after a few rounds of chemotherapy. This study addresses a critical unmet need for more effective TNBC therapies by targeting Salt-Inducible Kinase 2 (SIK2), which is overexpressed in 88% of TNBC specimens compared to normal breast tissue. We hypothesize that SIK2 inhibition could enhance paclitaxel efficacy and overcome resistance. In collaboration with Arrien Pharmaceuticals and Greenfire Biologics, we developed ARN-3261/GRN-300, a novel orally administered SIK2 inhibitor and evaluated its ability to sensitize TNBC cells to paclitaxel in vitro and in vivo. GRN-300 demonstrated strong synergy with paclitaxel in 8 of 9 TNBC cell lines tested, as indicated by combination indices. In xenograft models, the combination produced tumor growth inhibition and improved survival compared to either agent alone. Mechanistic studies showed that GRN-300 disrupts the APC/C pathway by downregulating key mitotic regulators, including CDC27, CDK1, and PLK1, resulting in enhanced G2/M arrest and apoptosis. Notably, GRN-300 retained activity in paclitaxel-resistant TNBC cell lines, suggesting the potential to overcome acquired resistance. Together, these findings establish GRN-300 as a promising first-in-class SIK2 inhibitor that augments paclitaxel efficacy through complementary disruption of mitotic pathways, providing strong preclinical rationale for clinical development in TNBC.
Advisory Committee:
- Robert Bast, MD, Chair
- Chandra Bartholomeusz, PhD
- Bisrat Debeb, DVM, PhD
- Catherine Denicourt, PhD
- Zhen Lu, MD