Clinical Application of Poly(ADP-Ribose) Polymerase (PARP) Inhibitors in Ovarian Cancer.

The treatment of ovarian cancer has remained a clinical challenge despite high rates of initial response to platinum-based chemotherapy. Patients are generally diagnosed at an advanced stage with significant disease burden, which portends to worse survival outcomes. Deficiencies in the homologous recombination (HRD) DNA damage repair (DDR) pathway and mutations in the BRCA1/2 genes have been found in ovarian carcinomas. Moreover, patients with these specific molecular aberrations have demonstrated sensitivity and thus improved response to poly(ADP-ribose) polymerase inhibitor (PARPi) treatment. The results of various clinical trials exploring the use of PARPi in different populations of ovarian cancer patients have shown impressive survival and response outcomes. With expanding indications, the use of PARPi has thus changed the landscape of ovarian cancer treatment. In this chapter, we will describe the different settings of PARPi treatment-frontline maintenance therapy, maintenance therapy for patients with recurrent platinum-sensitive disease, and treatment in the recurrent setting-and discuss treatment considerations and management of toxicities, as well as offer thoughts on future directions.

Transient Complete Atrioventricular Block Associated With Herbal Supplement Use.

INTRODUCTION: Increasing and easy availability of so-called natural/herbal supplements pose the unique challenge of identifying associated side effects, including arrhythmias in otherwise-healthy individuals. CASE PRESENTATION: A 25-year-old female patient presented to the emergency department with fatigue and lightheadedness. The electrocardiogram showed complete AV block with a junctional escape rhythm at 55 beats per minute with QT prolongation (542ms). One week ago, she started to use a herbal medication (Muscle Eze Advanced) for muscle cramps after workouts. Extensive cardiac testing, including complete blood count, complete metabolic panel, TSH, transthoracic echocardiography, urine drug analysis, Lyme antibody were negative. Normal sinus rhythm was restored spontaneously within 1 day of discontinuing the herbal medication. PR and corrected QT intervals returned to baseline over the next two weeks. CONCLUSION: Muscle Eze Advanced consists of seven ingredients, including Melissa officinalis and Valeriana officinalis that have negative chronotropic, negative dromotrophic and QT prolonging effects. Recognizing the association between certain over-the-counter supplements and brady-arrhythmias may circumvent need for permanent pacemakers - an important consideration especially in the young.

Targeting the PI3K Pathway in Gynecologic Malignancies.

PURPOSE OF REVIEW: This review explores the PI3K pathway aberrations common in gynecologic malignancies, the relevant therapeutic targets that have been explored to date particularly given their success in endometrial cancers, and predictive biomarkers of response to therapy. RECENT FINDINGS: Landmark trials have been noted involving this pathway, particularly in endometrial cancers. One phase II trial of the potent orally bioavailable mTOR inhibitor, everolimus, in combination with letrozole demonstrated an unprecedented clinical benefit rate (CBR) of 40% and high objective response rate (RR) of 32% in hormone agnostic endometrial cancers. This was followed by GOG 3007 that compared everolimus and letrozole to hormonal therapy yielding similar response rates but double progression-free survival rates. The phosphoinositide 3-kinase (PI3K) signaling pathway is implicated in tumorigenesis given its regulation over cell growth, cellular trafficking, and angiogenesis. In gynecologic malignancies, alterations in PI3K signaling are common. Therefore, developing modulators of the PI3K pathway and identifying molecular markers to predict response are of great interest for these cancer types.

Delayed Presentation of Inferior STEMI Complicated by Ventricular Septal Rupture: An Indirect Consequence of the COVID-19 Pandemic.

The COVID-19 pandemic has adversely impacted healthcare delivery. An indirect consequence of the rational fear of contracting the virus is delayed medical attention for life threatening conditions. We present the case of inferior ST elevation myocardial infarction leading to the rare complication of a ventricular septal rupture reflecting transmural infarction. COVID hesitancy caused a 48-hour delay in seeking medical attention after symptom onset. We also discuss the use of MRI to guide decision for timing of VSD repair in an otherwise asymptomatic patient post-revascularization.

The Clinical Challenges, Trials, and Errors of Combatting Poly(ADP-Ribose) Polymerase Inhibitors Resistance.

ABSTRACT: The use of poly(ADP-ribose) polymerase inhibitor (PARPi) exploits synthetic lethality in solid tumors with homologous recombination repair (HRR) defects. Significant clinical benefit has been established in breast and ovarian cancers harboring BRCA1/2 mutations, as well as tumors harboring characteristics of "BRCAness." However, the durability of treatment responses is limited, and emerging data have demonstrated the clinical challenge of PARPi resistance. With the expanding use of PARPi, the significance of PARP therapy in patients pretreated with PARPi remains in need of significant further investigation. Molecular mechanisms contributing to this phenomenon include restoration of HRR function, replication fork stabilization, BRCA1/2 reversion mutations, and epigenetic changes. Current studies are evaluating the utility of combination therapies of PARPi with cell cycle checkpoint inhibitors, antiangiogenic agents, phosphatidylinositol 3-kinase/AKT pathway inhibitors, MEK inhibitors, and epigenetic modifiers to overcome this resistance. In this review, we address the mechanisms of PARPi resistance supported by preclinical models, examine current clinical trials applying combination therapy to overcome PARPi resistance, and discuss future directions to enhance the clinical efficacy of PARPi.

Targeting the replication stress response through synthetic lethal strategies in cancer medicine.

The replication stress response (RSR) involves a downstream kinase cascade comprising ataxia telangiectasia-mutated (ATM), ATM and rad3-related (ATR), checkpoint kinases 1 and 2 (CHK1/2), and WEE1-like protein kinase (WEE1), which cooperate to arrest the cell cycle, protect stalled forks, and allow time for replication fork repair. In the presence of elevated replicative stress, cancers are increasingly dependent on RSR to maintain genomic integrity. An increasing number of drug candidates targeting key RSR nodes, as monotherapy through synthetic lethality, or through rational combinations with immune checkpoint inhibitors and targeted therapies, are demonstrating promising efficacy in early phase trials. RSR targeting is also showing potential in reversing PARP inhibitor resistance, an important area of unmet clinical need. In this review, we introduce the concept of targeting the RSR, detail the current landscape of monotherapy and combination strategies, and discuss emerging therapeutic approaches, such as targeting Polθ.

Development of poly(ADP-ribose) polymerase inhibitor and immunotherapy combinations: progress, pitfalls, and promises.

The efficacy of poly(ADP-ribose) polymerase inhibitors (PARPi) is restricted by inevitable drug resistance, while their use in combination with chemotherapy and targeted agents is commonly associated with dose-limiting toxicities. Immune checkpoint blockade (ICB) has demonstrated durable responses in different solid tumors and is well-established across multiple cancers. Despite this, single agent activity is limited to a minority of patients and drug resistance remains an issue. Building on the monotherapy success of both drug classes, combining PARPi with ICB may be a safe and well-tolerated strategy with the potential to improve survival outcomes. In this review, we present the preclinical, translational, and clinical data supporting the combination of DNA damage response (DDR) and ICB as well as consider important questions to be addressed with future research.

A Syngeneic Mouse Model of Epithelial Ovarian Cancer Port Site Metastases.

Epithelial ovarian cancer (EOC) is a deadly gynecologic malignancy, but animal models for the study of EOC pathophysiology and drug efficacy are limited. Based on the finding that women with EOC are at risk for metastasis at a trocar site after laparoscopy, we developed a syngeneic murine model of port-site metastasis of EOC. We leveraged the ID8 murine EOC cell line to induce intra-peritoneal tumors in mice. Once durable intraperitoneal tumor was confirmed with bioluminescence imaging, intra-abdominal wall tumors were induced by abdominal wall puncture with a hollow bore needle. This resulted in a robust system in which C57BL/6 mice developed metastatic deposits at a rate of 66.7% ±â€¯10.77; no intra-abdominal wall metastases were seen in control samples (P = .0003, CI 41.16-90.84). Immunodeficient NOD SCID gamma mice developed puncture site metastases in 70% ±â€¯10.0 of mice and also had no metastases documented in control sites (P = .002, CI 42.24-97.76). In addition we were able to demonstrate the presence of immune infiltrates within the metastatic deposits of C57BL/6 mice via IHC. Therefore, in this study we demonstrate the predictable development of invasive abdominal wall metastases in a syngeneic mouse model of EOC. This model enables studies of the metastatic process and provides a novel system in which to test the effect of therapies on a clinically-relevant model in an immune competent mouse.

Impact of audiovisual biofeedback on interfraction respiratory motion reproducibility in liver cancer stereotactic body radiotherapy.

INTRODUCTION: Irregular breathing motion exacerbates uncertainties throughout a course of radiation therapy. Breathing guidance has demonstrated to improve breathing motion consistency. This was the first clinical implementation of audiovisual biofeedback (AVB) breathing guidance over a course of liver stereotactic body radiotherapy (SBRT) investigating interfraction reproducibility. METHODS: Five liver cancer patients underwent a screening procedure prior to CT sim during which patients underwent breathing conditions (i) AVB, or (ii) free breathing (FB). Whichever breathing condition was more regular was utilised for the patient's subsequent course of SBRT. Respiratory motion was obtained from the Varian respiratory position monitoring (RPM) system (Varian Medical Systems). Breathing motion reproducibility was assessed by the variance of displacement across 10 phase-based respiratory bins over each patient's course of SBRT. RESULTS: The screening procedure yielded the decision to utilise AVB for three patients and FB for two patients. Over the course of SBRT, AVB significantly improved the relative interfraction motion by 32%, from 22% displacement difference for FB patients to 15% difference for AVB patients. Further to this, AVB facilitated sub-millimetre interfraction reproducibility for two AVB patients. CONCLUSION: There was significantly less interfraction motion with AVB than FB. These findings demonstrate that AVB is potentially a valuable tool in ensuring reproducible interfraction motion.

Assessment of voluntary deep inspiration breath-hold with CINE imaging for breast radiotherapy.

Deep Inspiration Breath-Hold (DIBH) techniques for breast cancer radiation therapy (RT) have reduced cardiac dose compared to Free Breathing (FB). Recently, a voluntary deep inspiration breath-hold (vDIBH) technique was established using in-room lasers and skin tattoos to monitor breath-hold. An in-house quality assessment of positional reproducibility during RT delivery with vDIBH in patients with left-sided breast cancer was evaluated. The electronic portal imaging device (EPID) was used in cinematographic (CINE) mode to capture a sequence of images during beam delivery. Weekly CINE images were retrospectively assessed for 20 left-sided breast cancer patients receiving RT in vDIBH, and compared with CINE images of 20 patients treated in FB. The intra-beam motion was assessed and the distance from the beam central axis (CA) to the internal chest wall (ICW) was measured on each CINE image. These were then compared to the planned distance on digitally reconstructed radiograph (DRR). The maximum intra-beam motion for any one patient measurement was 0.30 cm for vDIBH and 0.20 cm for FB. The mean difference between the distance from the CA to ICW on DRR and the equivalent distance on CINE imaging (as treated) was 0.28 cm (SD 0.17) for vDIBH patients and 0.25 cm (SD 0.14) for FB patients (P = 0.458). The measured values were comparable for patients undergoing RT in vDIBH, and for those in FB. This quality assessment showed that using in-room lasers and skin tattoos to independently monitor breath-hold in vDIBH as detected by 'on-treatment' CINE imaging is safe and effective.

Neurosteroid binding to the amino terminal and glutamate binding domains of ionotropic glutamate receptors.

The endogenous neurosteroids, pregnenolone sulfate (PS) and 3α-hydroxy-5ß-pregnan-20-one sulfate (PREGAS), have been shown to differentially regulate the ionotropic glutamate receptor (iGluR) family of ligand-gated ion channels. Upon binding to these receptors, PREGAS decreases current flow through the channels. Upon binding to non-NMDA or NMDA receptors containing an GluN2C or GluN2D subunit, PS also decreases current flow through the channels, however, upon binding to NMDA receptors containing an GluN2A or GluN2B subunit, flow through the channels increases. To begin to understand this differential regulation, we have cloned the S1S2 and amino terminal domains (ATD) of the NMDA GluN2B and GluN2D and AMPA GluA2 subunits. Here we present results that show that PS and PREGAS bind to different sites in the ATD of the GluA2 subunit, which when combined with previous results from our lab, now identifies two binding domains for each neurosteroid. We also show both neurosteroids bind only to the ATD of the GluN2D subunit, suggesting that this binding is distinct from that of the AMPA GluA2 subunit, with both leading to iGluR inhibition. Finally, we provide evidence that both PS and PREGAS bind to the S1S2 domain of the NMDA GluN2B subunit. Neurosteroid binding to the S1S2 domain of NMDA subunits responsible for potentiation of iGluRs and to the ATD of NMDA subunits responsible for inhibition of iGluRs, provides an interesting option for therapeutic design.