Our results suggest that ONC201 in combination with TRAIL may be an effective and non-toxic option for the treatment of gastric adenocarcinoma by inducing apoptosis via activation of the ISR, increased cell surface expression of DR5 and down-regulation of inhibitors of apoptosis. Our results demonstrate in vivo anti-tumor effects of ONC201 plus TLY012 against gastric cancer that could be further investigated in clinical trials.

JPI-547 is a novel PARP inhibitor, simultaneously targeting tankyrase1/2, other members of the PARP family, that are involved in the Wnt/β-catenin pathway. Antiproliferative effect of JPI-547 and a variety of PARP inhibitors (olaparib, veliparib, talazoparib, niraparib, and rucaparib) were determined by MTT assay or clonogenic assay in 9 human pancreatic ductal adenocarcinoma (PDAC) cell lines (Capan-1, HPAF-II, Capan-2, AsPC-1, SNU-410, SNU-213, SNU-324, MIA-PaCa2, and PANC-1). JPI-547 shows promising, preclinical antitumor effects against PDAC cells with HRD or Wnt-addiction, providing a rationale for further biomarker-driven clinical development of JPI-547 for the treatment of patients with PDAC.

Using established olaparib resistance models, the anti-tumor efficacy of JPI-547 was compared with olaparib, niraparib, and talazoparib. Then this suppression resulted in blockade of HR repair.JPI-547 showed promising efficacy in an olaparib-resistant preclinical model. JPI-547 merits further clinical development in the PARP inhibitor-resistant ovary and breast cancer.

The effective CI of ONC206 plus tazemetostat and panobinostat ranges 0.27-0.77 in U251 GBM and 0.11-0.71 in SU-DIPG-13 DMG cells...The effective CI of ONC212 plus valemetostat ranges 0.33-0.83 in 22Rv1...The synergies between ONC201 and EZH1/2 or HDAC inhibitors provide clues for developing novel therapy for the mentioned tumors. Overexpression of EZH2 is in process to elucidate the role of EZH2 in the mechanism of the anti-cancer effect of ONC201.

Our data provide evidence for synergy from the combination of ONC201 and ABT-263 against human solid tumor cell lines associated with alterations in cell death and pro-survival mediators. The combination of ONC201 and ABT-263 merits further exploration in vivo and in clinical trials against a variety of solid malignancies.

P2, N=30, Active, not recruiting, Allarity Therapeutics | Trial completion date: Oct 2022 --> May 2023 | Trial primary completion date: Oct 2022 --> Apr 2023

These results demonstrate that STP1002, a novel, orally active tankyrase inhibitor, shows preclinical antitumour efficacy without on-target toxicity in the GI tract. Our data provide a rationale for a clinical trial on STP1002 as a potential tankyrase-targeted drug in patients with APC-mutated CRC.

Our studies demonstrate that YAP/TAZ are major signaling molecules downstream of LOF AXIN1 mutant HCCs, and targeting YAP/TAZ as an effective treatment against AXIN1 mutant human HCCs.

P2, N=58, Not yet recruiting, Onconic Therapeutics Inc.

P2, N=30, Active, not recruiting, Allarity Therapeutics | Trial completion date: Oct 2021 --> Oct 2022 | Trial primary completion date: Oct 2021 --> Oct 2022

"Allarity Therapeutics, Inc...and Oncoheroes Biosciences, Inc...announced that they have entered into licensing agreements under which Oncoheroes will acquire exclusive, global development rights to Allarity’s therapeutic candidates dovitinib, a pan-targeted kinase inhibitor (pan-TKI), and stenoparib, a PARP inhibitor, and assume responsibility for their further clinical development in pediatric cancers...Under the terms of the licensing agreements, Oncoheroes acquires global, exclusive rights to fund and conduct further clinical development of both dovitinib and stenoparib in pediatric cancers...Allarity will support Oncoheroes’ pediatric clinical trials by providing clinical-grade drug inventory at cost and by facilitating DRP® companion diagnostic screening of pediatric patients for each drug...the Company is also planning a clinical trial of dovitnib in pediatric patients with osteosarcoma, in partnership with Oncoheroes..."

NBS1 overexpression in these cells inhibited the effects of low-dose etoposide/XAV939 treatment. Our results indicate that PARP5B inhibition is new targeted cancer therapy.

WNT signaling, NETO2 and PD1 + CD4 T cells are candidate biomarkers for predicting response to niraparib plus pembrolizumab. Further studies are underway to characterize the biological underpinnings of these correlative findings.

Opposing effects were observed following treatment with HLY78, which were ameliorated following co-treatment with DHA. Taken together, these results suggest that DHA or inhibition of TNKS can suppress the proliferation and migration of gastric cancer cells, which is partly associated with inactivation of the Wnt/β-catenin pathway and EMT process.

P2, N=30, Active, not recruiting, Allarity Therapeutics | Trial completion date: Apr 2021 --> Oct 2021 | Trial primary completion date: Apr 2021 --> Oct 2021

The TNKS1/2-specific inhibitor G007-LK was used to screen 537 human tumor cell lines and a panel of particularly TNKSi-sensitive tumor cell lines was identified...Moreover, we show that TNKSi induces accumulation of TNKS1/2-containing β-catenin degradasomes functioning as core complexes interacting with YAP and angiomotin proteins during attenuation of YAP signaling. These findings provide a contextual and mechanistic framework for using TNKSi in anticancer treatment that warrants further comprehensive preclinical and clinical evaluations.

miR-490-3p could affect colorectal cancer by targeting TNKS2. This study may provide a potential therapeutic target for colorectal cancer.

P2, N=30, Active, not recruiting, Oncology Venture | Trial completion date: Dec 2020 --> Apr 2021 | Trial primary completion date: Dec 2020 --> Apr 2021

P2, N=30, Active, not recruiting, Oncology Venture | Recruiting --> Active, not recruiting | Trial primary completion date: Sep 2020 --> Dec 2020

Moreover, microarray data analysis highlighted an overlap between miR-490 expression and REST-inhibition responses in GBM. Thus, miR-490-mediated targeting of telomere maintenance could be therapeutically important in GBM.

The hydrogen bonding of compounds with Asp1198, His1201, Tyr1203 in TNKS1 and Gly1032, Ser1068 in TNKS2 are the key interactions plays a major role in binding energy. Therefore, the outcome of the study would help for further validation and provides valuable information to guide the future tankyrase-specific inhibitor designing.

The results support further clinical investigation of E7449 and its associated biomarker 2X-121 DRP.

Previously, we reported the 2-mercaptoquinazolin-4-one MC2050 as a micromolar PARP1 inhibitor. Here we show how the resolution of the X-ray structure of PARP1 in complex with MC2050, combined with the computational investigation of the structural differences between TNKSs and PARP1/2 active sites, provided the rationale for a structure-based drug design campaign that with a limited synthetic effort led to the discovery of the bis-quinazolinone 5 as a picomolar and selective TNKS2 inhibitor, endowed with antiproliferative effects in a colorectal cancer cell line (DLD-1) where the Wnt pathway is constitutively activated.

P2; N=30; Recruiting; Sponsor: Oncology Venture