Quisinostat is an orally bioavailable potent histone deacetylase inhibitor (HDAC1), specifically selected due to its sustained inhibition of HDAC1 in solid tumor tissues and prolonged period of half-elimination from tissues. The drug is being developed in collaboration with Janssen Pharmaceutica NV.
Phase 2 clinical trials are ongoing in patients with platinum-resistant ovarian cancer and non-small cell lung cancer (NSCLC).
Ovarian cancer is the ninth most common cancer and accounts for 3% of all cancers in women. Ovarian cancer ranks as the fifth most frequent cause of death by cancer among women, accounting for more deaths than any other cancer of the female reproductive system. One out of every 71 women is at risk of developing ovarian cancer, and one out of every 95 women dies from ovarian cancer.
NSCLC presents significant public health problems for nearly every country, largely because of the fact that diagnosis generally happens in the advanced stages, and the high death rate associated with the disease. The number of people with NSCLC remains stable and only a very modest increase in the number of total incident cases is expected from more than 465,000 diagnosed incident cases in 2010 to nearly 569,000 in 2020.
NewVac is investigating several combinations of Quisinostat with proteasome inhibitors to treat synovial and translocation-associated sarcomas in adolescents and young adults.
Synovial and translocation –associated sarcomas are aggressive soft-tissue malignancies with high risk of early and late metastases. Long-term disease-specific mortality rates of ~50% (Synovial Sarcoma), 65% (Clear Cell Sarcoma), 15% (Myxoid Liposarcoma), 85% (Desmoplastic Small Roubd Cell Tumor, Ewing Sarcome)
The underlying mechanism of these deadly tumors is described. The driving mutation is translocation event between the SS18 gene on chromosome 18 and one of 3 SSX genes (SSX1, SSX2 and SSX4) on chromosome X:
ti(X;18) -> SS18/SSX, that forms a fusion oncoprotein complex that represses cell differentiation and puts down tumor suppressors.
HDAC1 inhibitor Quisinostat interacts with SS18/SSX; Quisinostat depresses SS18-SSX target genes in Synovial Sarcomas and other fusion oncoprotein complexes in CCS (EWS/ATF1), in MLS (FUS/DDIT3) and in DSRCT (EWS/WT1).
Pre-clinical and early clinical studies demonstrate that combination of Quisinostat with proteasome inhibitors induces significant apoptosis in synovial and other translocation- associated sarcomas. NewVac LLC works to prove that this combination is a breakthrough in sarcoma treatment.
Combination of Qusinostat with check-point inhibitors.
Combination of Quisinostat with check point inhibitors ( anti-PD1, anti – PD-L and anti-CTLA4) offers a new possibility for effective onco-immunology treatment. Several HDAC-checkpoint combination trials are running at the moment. The early results suggest that treatment is well tolerated and effective in late stage m NSCLC, renal cell carcinoma, OC, triple-negative BC and melanoma. Through blocking the immuno-suppressive effects of MDSCs and Treg cells, quisinostat has the potential of synergy with therapies such as immune checkpoint inhibitors, resulting in the increased ability of the T cells to attack the tumor.
We believe that combining checkpoint inhibitors with Quisinostat might benefit the patients with platinum-resistant cancers, raising the response rate and duration of the response.