Browsing by Author "Damayanti, Nur"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    EXTH-43. Targeting the DNA Damage Response Through Combination MDM2 and AKT Inhibitor Therapy Improves Temozolomide Effectiveness in Chemo-Resistant Glioblastoma
    (Oxford University Press, 2023-11-10) Koenig, Jenna; Bailey, Barbara; Alfonso, Anthony; Saadatzadeh, M. Reza; Bijangi-Vishehsaraei, Khadijeh; Pandya, Pankita; Damayanti, Nur; Dobrota, Erika; Young, Courtney; Shannon, Harlan; Pollok, Karen; Graduate Medical Education, School of Medicine
    Temozolomide remains the lone pharmacotherapeutic option for glioblastoma (GBM), yet the development of resistance to temozolomide has been a major challenge contributing to the persistent median < 2-year survival for patients after diagnosis. Tumor heterogeneity and induction of treatment response networks, such as the DNA damage response (DDR), are major contributors to temozolomide resistance in GBM. Targeting DDR treatment response networks, such as the MDM2/p53/p73 and PI3K/AKT/mTOR networks, with small-molecule inhibitors (SMIs) presents an opportunity to disrupt resistance mechanisms and enhance temozolomide efficacy. We utilized a triple drug combination of clinically relevant concentrations of the blood-brain-barrier penetrant SMIs of AKT (ipatasertib; GDC-0068) and MDM2 (idasanutlin; RG7388) with temozolomide to evaluate this targeted strategy using the recurrent, temozolomide-resistant, p53wt GBM10 xenoline. Proliferation studies demonstrated dose-related additive to synergistic inhibition of proliferation at clinically relevant concentrations of ipatasertib and idasanutlin. Further, IncuCyte live-cell imaging demonstrated dose-and time-related growth inhibition of these GBM cells and apoptosis marked by increased cleaved caspase 3 expression following the temozolomide+idasanutlin+ipatasertib triple combination treatment. Cells treated with temozolomide+idasanutlin+ipatasertib also displayed senescence phenotypes, with increased cell cycle arrest and elevated expression of SPiDER β-Gal expression and cell-cycle inhibitors such as p53 and p21. Experiments are in progress to determine the extent to which the effects of temozolomide+idasanutlin+ipatasertib combination therapy are dependent on p53 using siRNA knockdown of p53. In the present study, targeting the temzolomide-induced DNA damage response with idasanutlin+ipatasertib increased the effectiveness of temozolomide. These results indicate that this triple combination may be a promising approach to improving patient outcomes in temozolomide-resistant GBM.
  • Thumbnail Image
    Item
    Phase I study of the mTOR inhibitor everolimus in combination with the histone deacetylase inhibitor panobinostat in patients with advanced clear cell renal cell carcinoma
    (SpringerLink, 2020-08) Wood, Anthony; George, Saby; Adra, Nabil; Chintala, Sreenivasulu; Damayanti, Nur; Pili, Roberto; Medicine, School of Medicine
    Background: Preclinical studies suggested synergistic anti-tumor activity when pairing mTOR inhibitors with histone deacetylase (HDAC) inhibitors. We completed a phase I, dose-finding trial for the mTOR inhibitor everolimus combined with the HDAC inhibitor panobinostat in advanced clear cell renal cell carcinoma (ccRCC) patients. We additionally investigated expression of microRNA 605 (miR-605) in serum samples obtained from trial participants. Patients and Methods: Twenty-one patients completed our single institution, non-randomized, open-label, dose-escalation phase 1 trial. miR-605 levels were measured at cycle 1/day 1 (C1D1) and C2D1. Delta Ct method was utilized to evaluate miR-605 expression using U6B as an endogenous control. Results: There were 3 dosing-limiting toxicities (DLTs): grade 4 thrombocytopenia (n = 1), grade 3 thrombocytopenia (n = 1), and grade 3 neutropenia (n = 1). Everolimus 5 mg PO daily and panobinostat 10 mg PO 3 times weekly (weeks 1 and 2) given in 21-day cycles was the recommended phase II dosing based on their maximum tolerated dose. The 6-month progression-free survival was 31% with a median of 4.1 months (95% confidence internal; 2.0-7.1). There was higher baseline expression of miR-605 in patients with progressive disease (PD) vs those with stable disease (SD) (p = 0.0112). PD patients' miR-605 levels decreased after the 1st cycle (p = 0.0245), whereas SD patients' miR-605 levels increased (p = 0.0179). Conclusion: A safe and tolerable dosing regimen was established for combination everolimus/panobinostat therapy with myelosuppression as the major DLT. This therapeutic pairing did not appear to improve clinical outcomes in our group of patients with advanced ccRCC. There was differential expression of miR-605 that correlated with treatment response.