Ovarian Cancer Early Detection
Identification of biomarkers and strategies for early detection of ovarian cancer
Ovarian cancer is a leading cause of cancer death from gynecologic malignancies that is diagnosed each year in more than 300,000 women worldwide and in 19,880 from the United States alone. Despite advances in treatment, 70-75% of women with ovarian cancer are diagnosed with advanced stage (III or IV) where the cure rate is less than 30%. Although computer algorithms suggest that mortality could be reduced by 10-30% if ovarian cancers were detected at an earlier stage, only 25-30 % of patients are currently diagnosed in stage I or II. Having developed the first monoclonal antibodies that react with epithelial ovarian cancer, including OC125, my group had discovered the CA125 antigen, leading to the development of the first clinically useful biomarker for monitoring ovarian cancer. In recent years, we have identified a panel of four serum biomarkers, including CA125, which detects more than 80% of early-stage ovarian cancer. Anti-TP53 autoantibodies have been shown to detect 20% of cases missed by CA125 and to increase 8 months prior to CA125 or 22 months prior to diagnosis when CA125 is not elevated. In the 21-year NROSS ovarian cancer screening trial, rising CA125 followed by transvaginal ultrasound detected 74% of ovarian cancers with 70% in early stage (I-II) requiring only 2 operations to detect each case and producing a stage shift of >30% . Using a 4-biomarker (CA125, HE4, HE4 Ag-Ab and OPN) algorithm advanced stage disease can be detected 1-4 years earlier and a new 5-year screening trial has been funded by the NCI EDRN .
NCI EDRN (U01 CA200462; Bast, PI)
(R01 CA247220, Lokshin and Bast, PI’s)
Individualized enhancement of primary sensitivity to paclitaxel in ovarian cancer.
Most ovarian cancer patients receive a combination of carboplatin and paclitaxel chemotherapy, but less than half respond to paclitaxel. Enhanced response to primary chemotherapy could improve outcomes in the majority of non-responders by combining targeted therapy with paclitaxel. Through high throughput Kinome siRNA screen, we identified more than 30 kinases that regulate paclitaxel sensitivity in ovarian cancer cells. Knockdown of kinases such as IKBKB and STK39 enhance paclitaxel sensitivity by increasing microtubule stability regulated by microtubule associated protein 4 (MAP4). Knockdown of kinases that modulate the pentose phosphate shunt such as PFKFB2 also enhance the response to paclitaxel in ovarian and breast cancer cells with wild type TP53. Knockdown of Salt-inducible Kinase 2 (SIK2) enhanced sensitivity to paclitaxel, inducing polyploidy and inhibiting PI3K activity. SIK2 encodes an AMP-like kinase that is overexpressed in 30% of ovarian cancers, associated with decreased survival. We discovered that SIK2 localizes to the centrosome and is required for centrosome splitting. It also regulates PI3 kinase activity and class IIa HDAC phosphorylation and nuclear localization. SIK2 has been targeted with siRNA in nanoparticles and with the low molecular weight inhibitors ARN-3236 and GRN-300. A phase I clinical trial of a SIK2 inhibitor (GRN-300) with paclitaxel is underway with little toxicity Combinations of GRN-300 with PARP inhibitors and ICB are being tested to overcome drug resistance.
Ovarian SPORE (P50CA28170; Sood and Bast, PI’s)
(ACS SRA-22-193, Bast, PI)
Tumor Suppressor and Dormancy
DIRAS3 is an imprinted tumor suppressor gene that is down-regulated in ovarian cancers through genetic and epigenetic mechanisms
DIRAS3 is an imprinted tumor suppressor gene that encodes a 26 kDa GTPase with 60% amino acid homology to RAS, but with a distinctive 34 amino acid N-terminal extension required to block RAS function. DIRAS3 is maternally imprinted and expressed only from the paternal allele in normal cells. Loss of expression can occur in a single "hit" through multiple mechanisms. Downregulation of DIRAS3 occurs in cancers of the ovary, breast, lung, prostate, colon, brain, and thyroid. Reexpression of DIRAS3 inhibits signaling through PI3 kinase/AKT, JAK/STAT, and RAS/MAPK, blocking malignant transformation, inhibiting cancer cell growth and motility, and preventing angiogenesis. DIRAS3 is essential for autophagy and triggers this process through multiple mechanisms. Reexpression of DIRAS3 induces dormancy in a nu/nu mouse xenograft model of ovarian cancer, inhibiting cancer cell growth and angiogenesis. DIRAS3-mediated induction of autophagy facilitates the survival of dormant cancer cells in a nutrient-poor environment. DIRAS3 expression in dormant, drug-resistant autophagic cancer cells can serve as a biomarker and as a target for novel therapy to eliminate the residual disease that remains after conventional therapy. . DIRAS3 is a unique endogenous RAS inhibitor that binds directly to RAS, disrupting RAS dimers and clusters, and preventing RAS-induced transformation. DIRAS3 related stapled peptides enter cells, disrupt RAS signaling, inhibit tumor growth and enhance response to autophagy inhibitors.
(R01CA266187, Bast and Lu, PI’s)