PARP Inhibition in Cancer: An Update on Clinical Development.

PARP (poly(ADP-ribose) polymerase) inhibitors represent a novel class of anti-cancer therapy; they take advantage of synthetic lethality and induce cell death by exploiting a defect in DNA repair. This class of medication was initially evaluated in patients with BRCA-associated tumors, but efficacy was also demonstrated in other populations. Since 2014, four PARP inhibitors have been approved in various indications: olaparib, niraparib, and rucaparib in high-grade serous ovarian cancer, and olaparib and talazoparib in metastatic breast cancer. The exact indications and study populations vary slightly between the different approvals in both disease states but there is significant overlap. PARP inhibitors continue to be investigated in ongoing clinical trials. In line with other targeted therapies, benefit appears to be strongest in a distinct population of patients with BRCA mutations or other defects in homologous recombination repair. Combination therapies, which include anti-angiogenesis agents and immunotherapy, show promise as a strategy to broaden efficacy for unselected patients. Initial studies of PARP inhibitors in combination with chemotherapy were limited by toxicity, but further studies are underway. To date, head-to-head trials comparing various PARP inhibitors have not been conducted, so questions remain in terms of choosing a PARP inhibitor to administer when indications overlap, as well as how to sequence these medications. Here we review both completed and ongoing clinical trials involving PARP inhibitors and mechanisms of resistance to this class of drugs.

Targeting the Wnt Pathway in Cancer: A Review of Novel Therapeutics.

Wnt signaling is an evolutionarily conserved pathway that controls cell-to-cell interactions during embryogenesis. In adults, Wnt signaling plays a role in tissue homeostasis in almost every organ system. Aberrations within this pathway are implicated in a spectrum of human diseases. A variety of perturbations have been described in both solid and hematologic malignancies, lending way to Wnt signaling as a target for anti-cancer therapy. Of particular interest is the role of Wnt signaling in the development and maintenance of cancer stem cells, a rare population of cells that are able to maintain a tumor via self-renewal and thought to be more resistant to chemotherapy than bulk tumor cells. The ability to eradicate cancer stem cells may decrease the risk of cancer relapse and metastasis. A number of therapeutic agents specifically targeting the Wnt pathway have entered clinical trials, either as monotherapy or in combination with chemotherapy. We will provide an overview of agents that have been developed to target the Wnt pathways and a summary of pre-clinical and clinical trials.

The yield of endometrial aspiration in women with various risk factors and bleeding abnormalities.

BACKGROUND: Even in the face of a substantial increase in the numbers of endometrial cancer cases and in the numbers of women who have risk factors, there is no clear agreement about the indications for assessing the endometria of women with abnormal bleeding or about the tools to use in that assessment. This study sought to determine in a group of high risk women with abnormal uterine bleeding, the probability that an outpatient endometrial aspiration would identify significant pathology. METHODS: Retrospective cohort study of the histology from endometrial aspirations performed from 2001 to 2008 for abnormal uterine bleeding at Harbor-UCLA Medical Center and its satellite public health clinics. Medical records were reviewed in detail to assess risk factors, descriptions of bleeding abnormalities and histologic results. RESULTS: The charts of 1601 women who underwent 1636 endometrial biopsies for a wide variety of abnormal uterine bleeding patterns yielded 73 (4.6 %) cases of endometrial carcinoma, 43 cases of atypical endometrial hyperplasia (2.7 %), for an overall yield of significant pathology of 7.2 %. Hyperplasia without atypia was found in another 83 cases (5.2 %). Obesity, diabetes and postmenopausal age are associated with an increased risk of significant pathology. Bleeding patterns were so poorly documented that analysis of yield by this factor should be viewed with caution. CONCLUSIONS: The probability of detecting significant uterine pathology is greatest among obese, diabetic postmenopausal women with diabetes (26.3 %). Conversely, the probability of identifying significant pathology in younger women without risk factors is less than 2 %. For women who perceive their individualized risk estimate to be too small to justify an endometrial biopsy, it may be possible to offer oral higher dose progestin therapy on the condition that persistent abnormal bleeding will require more intensive evaluation. These estimates of absolute risk of being diagnosed with significant pathology on endometrial biopsy may be helpful to patients as they consider giving informed consent for the procedure.