Efficacy In Cancer Xenograft Models Research Articles

Damage Incorporated: Discovery of the Potent, Highly Selective, Orally Available ATR Inhibitor BAY 1895344 with Favorable Pharmacokinetic Properties and Promising Efficacy in Monotherapy and in Combination Treatments in Preclinical Tumor Models.

The ATR kinase plays a key role in the DNA damage response by activating essential signaling pathways of DNA damage repair, especially in response to replication stress. Because DNA damage and replication stress are major sources of genomic instability, selective ATR inhibition has been recognized as a promising new approach in cancer therapy. We now report the identification and preclinical evaluation of the novel, clinical ATR inhibitor BAY 1895344. Starting from quinoline 2 with weak ATR inhibitory activity, lead optimization efforts focusing on potency, selectivity, and oral bioavailability led to the discovery of the potent, highly selective, orally available ATR inhibitor BAY 1895344, which exhibited strong monotherapy efficacy in cancer xenograft models that carry certain DNA damage repair deficiencies. Moreover, combination treatment of BAY 1895344 with certain DNA damage inducing chemotherapy resulted in synergistic antitumor activity. BAY 1895344 is currently under clinical investigation in patients with advanced solid tumors and lymphomas (NCT03188965).

The Novel ATR Inhibitor BAY 1895344 Is Efficacious as Monotherapy and Combined with DNA Damage-Inducing or Repair-Compromising Therapies in Preclinical Cancer Models.

The DNA damage response (DDR) secures the integrity of the genome of eukaryotic cells. DDR deficiencies can promote tumorigenesis but concurrently may increase dependence on alternative repair pathways. The ataxia telangiectasia and Rad3-related (ATR) kinase plays a central role in the DDR by activating essential signaling pathways of DNA damage repair. Here, we studied the effect of the novel selective ATR kinase inhibitor BAY 1895344 on tumor cell growth and viability. Potent antiproliferative activity was demonstrated in a broad spectrum of human tumor cell lines. BAY 1895344 exhibited strong monotherapy efficacy in cancer xenograft models that carry DNA damage repair deficiencies. The combination of BAY 1895344 with DNA damage-inducing chemotherapy or external beam radiotherapy (EBRT) showed synergistic antitumor activity. Combination treatment with BAY 1895344 and DDR inhibitors achieved strong synergistic antiproliferative activity in vitro, and combined inhibition of ATR and PARP signaling using olaparib demonstrated synergistic antitumor activity in vivo Furthermore, the combination of BAY 1895344 with the novel, nonsteroidal androgen receptor antagonist darolutamide resulted in significantly improved antitumor efficacy compared with respective single-agent treatments in hormone-dependent prostate cancer, and addition of EBRT resulted in even further enhanced antitumor efficacy. Thus, the ATR inhibitor BAY 1895344 may provide new therapeutic options for the treatment of cancers with certain DDR deficiencies in monotherapy and in combination with DNA damage-inducing or DNA repair-compromising cancer therapies by improving their efficacy.

Abstract LB-159: A novel, potent and selective inhibitor of Wee1 with robust antitumor activity in various cancer xenograph models

Abstract Wee1 is a tyrosine kinase that phosphorylates cyclin-dependent kinase 1 (CDK1/CDC2) to inactive the CDC2/cyclinB complex. Wee1 is therefore a key regulator of the cell cycle, maintaining the G2 checkpoint arrest to allow for premitotic repair in case of DNA damage. Unlike normal cells, most p53-deficient tumors lack a functional G1 checkpoint and instead rely on the G2 checkpoint for DNA repair. Abrogation of the G2 checkpoint by a Wee1 inhibitor may therefore sensitize p53-deficient tumors to DNA-damaging anticancer agents and enhance their cytotoxic effect. Strong evidence for chemo-sensitization has been demonstrated from multiple pre-clinical models and also from clinical trials. In particular, treatment in combination with carboplatin recently showed encouraging antitumor activity in patients with p53-mutated ovarian cancer refractory or resistant to standard first-line therapy. These clinical observations combined with recent reports demonstrating single agent efficacy in specific contexts make Wee1 a promising target for anticancer therapy. With only one inhibitor in clinical development (AZD1775) and very limited reports at the preclinical stage, the development of alternative, novel Wee1 inhibitors may have significant therapeutic value. In this study, we describe the development and characterization of ADC730, a potent and highly selective small molecule Wee1 inhibitor. ADC730 inhibits Wee1 kinase activity with an IC50 of <5 nM and demonstrates excellent selectivity when profiled against a diverse panel of kinases. In cellular assays, ADC730 potently inhibited CDC2-dependent Wee1 phosphorylation. Further studies in a panel of cancer cell lines demonstrated strong anti-proliferative activity of ADC730 both in combination with gemcitabine or in monotherapy modalities. Single agent activity was observed in multiple cancer types including lung and kidney. gH2AX foci formation followed by apoptosis induction were typically observed in a dose-dependent manner for the most sensitive cell lines. In vivo, oral administration of ADC730 (10, 30 mg/kg/day) in combination with gemcitabine caused a significant dose-dependent growth reduction of HT29 tumors and the combination was synergistic. ADC730 was well tolerated in all cases with no signs of adverse effects. Dosed orally as a single agent (10, 30 mg/kg/day), ADC730 also demonstrated robust dose-dependent anti-tumor efficacy in the A427 lung carcinoma model with inhibition of tumor growth consistent with the pharmacodynamic modulation of Wee1 signaling. In comparison and under similar experimental conditions, AZD1775 demonstrated similar efficacy profiles at significantly higher doses. To conclude, we describe the development and profiling towards candidate nomination of ADC730, a novel potent highly selective Wee1 inhibitor with robust efficacy in cancer xenograft models both in combination and single agent modalities. Subsequent analogs and examples with potentially enhanced profiles will also be described. Citation Format: Gerald Gavory, Colin O’Dowd, Frank Burkamp, Shane Rountree, Ewelina Rozycka, Caroline Boyd, Beronia Gorges, Stephanie Burton, Andy Wilkinson, Steven Shepherd, Dominic Janssen, Mary McFarland, Shane Rountree, Tim Harrison. A novel, potent and selective inhibitor of Wee1 with robust antitumor activity in various cancer xenograph models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-159.

OGX-427 inhibits tumor progression and enhances gemcitabine chemotherapy in pancreatic cancer

Despite many advances in oncology, almost all patients with pancreatic cancer (PC) die of the disease. Molecularly targeted agents are offering hope for their potential role in helping translate the improved activity of combination chemotherapy into improved survival. Heat shock protein 27 (Hsp27) is a chaperone implicated in several pathological processes such as cancer. Further, Hsp27 expression becomes highly upregulated in cancer cells after chemotherapy. Recently, a modified antisense oligonucleotide that is complementary to Hsp27 (OGX-427) has been developed, which inhibits Hsp27 expression and enhances drug efficacy in cancer xenograft models. Phase II clinical trials using OGX-427 in different cancers like breast, ovarian, bladder, prostate and lung are in progress in the United States and Canada. In this study, we demonstrate using TMA of 181 patients that Hsp27 expression and phosphorylation levels increase in moderately differentiated tumors to become uniformly highly expressed in metastatic samples. Using MiaPaCa-2 cells grown both in vitro and xenografted in mice, we demonstrate that OGX-427 inhibits proliferation, induces apoptosis and also enhances gemcitabine chemosensitivity via a mechanism involving the eukaryotic translation initiation factor 4E. Collectively, these findings suggest that the combination of Hsp27 knockdown with OGX-427 and chemotherapeutic agents such as gemcitabine can be a novel strategy to inhibit the progression of pancreas cancer.