Thomas Rutherford

PARP Inhibitors in Ovarian Cancer: Resistance Mechanisms, Clinical Evidence, and Evolving Strategies

The introduction of poly (ADP-ribose) polymerase inhibitors (PARPi) into the management of ovarian cancer has transformed the treatment landscape for patients affected by this malignancy. However, as the use of PARPi expands into both frontline maintenance and recurrence settings, the emergence of drug resistance has become a significant clinical challenge in the treatment of these patients. Although platinum-based chemotherapy (PBC) and PARPi act through different mechanisms—PBC causes DNA damage while PARPi blocks its repair—both depend on the integrity of DNA damage repair (DDR) pathways, leading to overlapping mechanisms of resistance. Here, we review the key resistance mechanisms shared by PARPi and PBC, and then we discuss their clinical implications in the management of patients with ovarian cancer. We also examine clinical rationale supporting the hypothesis that prior PARPi exposure may reduce the efficacy of subsequent PBC in patients experiencing a disease recurrence. Furthermore, we review preliminary clinical data assessing the potential role of PARPi retreatment in patients who have previously progressed on PARPis.

Spatially restricted ecto‐5′‐nucleotidase expression promotes the growth of uterine leiomyomas by modulating Akt activity

Abstract Found in as many as 80% of women, uterine leiomyomas are a frequent cause of abnormal uterine bleeding, pelvic pain, and infertility. Despite their significant clinical impact, the mechanisms responsible for driving leiomyoma growth remain poorly understood. After obtaining IRB permission, expression of ecto‐5′‐nucleotidase ( NT5E, CD73 ) was assessed in matched specimens of myometrium and leiomyoma by real‐time qPCR, Western blot, and immunohistochemistry (IHC). Adenosine concentrations were measured by enzyme‐linked assay. Primary cultures were used to assess the impact of adenosine and/or adenosine receptor agonists on proliferation, apoptosis, and patterns of intracellular signaling in vitro. When compared to matched specimens of healthy myometrium, uterine leiomyomas were characterized by reduced CD73 expression. Largely limited to thin‐walled vascular structures and the pseudocapsule of leiomyomas despite diffuse myometrial distribution. Restricted intra‐tumoral CD73 expression was accompanied by decreased levels of intra‐tumoral adenosine. In vitro, incubation of primary leiomyoma cultures with adenosine or its hydrolysis‐resistant analog 2‐chloro‐adenosine (2‐CL‐AD) inhibited proliferation, induced apoptosis, and reduced proportion of myocytes in S‐ and G2‐M phases of the cell cycle. Decreased proliferation was accompanied by reduced expression of phospho‐Akt, phospho‐Cdk2‐Tyr15, and phospho‐Histone H3. Enforced expression of the A2B adenosine receptor (ADORA2B) and ADORA2B‐selective agonists similarly suppressed proliferation and inhibited Akt phosphorylation. Collectively, these observations broadly implicate CD73 and reduced extracellular concentrations of adenosine as key regulators of leiomyoma growth and potentially identify novel strategies for clinically managing these common tumors.

Immune Modulation of Innate and Adaptive Responses Restores Immune Surveillance and Establishes Antitumor Immunologic Memory

Abstract Current immunotherapies have proven effective in strengthening antitumor immune responses, but constant opposing signals from tumor cells and the surrounding microenvironment eventually lead to immune escape. We hypothesized that in situ release of antigens and regulation of both the innate and adaptive arms of the immune system would provide a robust and long-term antitumor effect by creating immunologic memory against tumors. To achieve this, we developed CARG-2020, a genetically modified virus-like vesicle (VLV) that is a self-amplifying RNA with oncolytic capacity and encodes immune regulatory genes. CARG-2020 carries three immune modulators: (i) the pleiotropic antitumor cytokine IL12, in which the subunits (p35 and p40) are tethered together; (ii) the extracellular domain (ECD) of the protumor IL17RA, which serves as a dominant-negative antagonist; and (iii) a shRNA targeting PD-L1. Using a mouse model of ovarian cancer, we demonstrated the oncolytic effect and immune-modulatory capacities of CARG-2020. By enhancing IL12 and blocking IL17 and PD-L1, CARG-2020 successfully reactivated immune surveillance by promoting M1, instead of M2, macrophage differentiation, inhibiting MDSC expansion and establishing a potent CD8+ T cell–mediated antitumoral response. Furthermore, we demonstrated that this therapeutic approach provided tumor-specific and long-term protection against the establishment of new tumors. Our results provide a rationale for the further development of this platform as a therapeutic modality for ovarian cancer patients to enhance antitumor responses and prevent a recurrence.