DelMar Pharmaceuticals, Inc. (OTCQX: DMPI) ("DelMar" and the "Company"), a biopharmaceutical company focused on the development and commercialization of new cancer therapies, announced that yesterday it presented positive preclinical data demonstrating the promising potential of its lead product candidate VAL-083 (dianhydrogalactitol) as a treatment for ovarian cancer.
The Company presented data from its collaboration with researchers at MD Anderson Cancer Center in a poster entitled, "A Comparison of the Mechanisms and Cytotoxic Activity of Dianhydrogalactitol (VAL-083) to Cisplatin in Ovarian Tumor Models Harboring Wild-type and Mutant p53," at the American Association for Cancer Research (AACR) Advances in Ovarian Cancer Research: Exploiting Vulnerabilities Conference.
The data demonstrate the effectiveness of VAL-083 against cisplatin-resistant ovarian cancers and raise the potential for VAL-083 as a treatment for ovarian cancers as a single-agent against platinum-resistant tumors or in combination with platinum-based chemotherapeutic regimens.
VAL-083 is a bi-functional alkylating agent, whose cytotoxic activity is due to the formation of DNA cross links at the N7 position of guanine. Unlike platinum-based chemotherapies such as cisplatin, carboplatin and oxaliplatin, which predominantly form intrastrand DNA cross-links, VAL-083 is believed to derive its anti-cancer activity via interstrand DNA cross-links, which leads to a distinct downstream of biological events within the tumor leading to apoptosis and cancer cell death. In prior NCI-sponsored clinical studies, VAL-083 demonstrated clinical activity against a range of tumor types, including ovarian cancer.
"These data represent another success in our strategy to leverage VAL-083's historical clinical data with contemporary biological research to address significant unmet medical needs in the modern treatment of cancer," stated Jeffrey Bacha, president & CEO of DelMar Pharmaceuticals.
"Onset of drug resistance is a major factor limiting the clinical utility of platinum-based therapeutic regimens. Such regimens form the basis of ovarian cancer treatment and produce an initial 70% response rate. Unfortunately, many patients experience relapse as their cancer becomes resistant to currently available chemotherapy. The average duration of survival after recurrence of ovarian cancer is about 12 to 18 months with fewer than one in ten patients surviving beyond five years following standard salvage chemotherapy treatment," added Mr. Bacha. "We believe that these data, coupled with evidence of historical clinical activity against ovarian cancer, represent the promise of VAL-083 to address a major modern unmet medical need by providing a potential new treatment option for ovarian cancer patients whose tumors exhibit resistance to platinum-based therapy."
Platinum drug resistance is normally ascribed to several mechanisms. The current study investigated the activity of VAL-083 in multiple ovarian cancer models including both cisplatin-sensitive (A2780); and cisplatin-resistant (2780CP-16, OVCAR-10, Hey and OVCA-433) phenotypes in vitro. The data support the potential of VAL-083 to circumvent drug-resistance in the treatment of ovarian cancer.
DelMar previously reported that the combination of VAL-083 and cisplatin demonstrated significant super-additivity (p<0.05) in animal models of non-small cell lung cancer (NSCLC) and synergy (CI < 1) in vitro.
Mr. Bacha continued, "We have a growing body of evidence indicating that, in comparison to platinum-based chemotherapy, the anti-cancer mechanism of VAL-083 is less dependent on, or independent of, wild-type p53. The current ovarian study provides additional proof that there is a lack of cross-resistance between cisplatin and VAL-083 further suggesting distinct modes of action for the two drugs. Importantly, the non-overlapping mechanisms of action support the potential of VAL-083 in the treatment of platinum-resistant cancers as well as the potential for therapeutic benefit in combining VAL-083 with platinum-based chemotherapy regimens."
HIGHLIGHTS OF DELMAR'S PRESENTATION
- VAL-083 demonstrated cytotoxic activity in all tested ovarian cancer cell lines, including cisplatin-resistant cell lines, in vitro;
- VAL-083 is significantly less dependent on wild-type p53 for its activity than both cisplatin and oxaliplatin, and appears to have a distinct mode of action;
- VAL-083 exhibits significantly different cytotoxic-related cell-signaling patterns against resistant tumor phenotypes in comparison to platinum-based chemotherapy, in vitro;
- VAL-083 displays significant synergy with cisplatin in vitro; and
- Taken together, these results support VAL-083 as a viable treatment option for ovarian cancer patients failing platinum-based therapy, and suggests a potential benefit of a VAL-083 + platinum combination therapy.
VAL-083 activity in five wild-type p53 ovarian cancer cell lines
The activity of VAL-083 was examined in five ovarian cancer cell lines: including one cisplatin-sensitive (A2780), and four cisplatin-resistant (2780CP-16, OVCAR-10, Hey and OVCA-433) tumors in vitro. The relative tumor-killing effect (IC50) was compared in cisplatin-sensitive versus cisplatin-resistant cell-lines. VAL-083 maintained significantly greater cytotoxic activity in comparison to cisplatin. These results demonstrate a lack of significant cross-resistance between cisplatin and VAL-083, further suggesting distinct modes of action for VAL-083.
Limited dependence of VAL-083 on p53 status
The dependence on p53 status was investigated in isogenic models with (HCT-116p53-/-) or without (HCT-116p53+/+) p53 knockout. Loss of p53 increased resistance to cisplatin and oxaliplatin by 3- and 6-fold, respectively, whereas the increase in resistance to VAL-083 was <2-fold. These data suggest that the cytotoxic a mechanism of VAL-083 that is much less dependent on, or independent of, p53.
VAL-083 signaling is distinct from platinum-based chemotherapy in drug-resistant ovarian tumors
Resistance to platinum-based chemotherapy can also arise in tumors bearing wild-type (non-mutant) p53 due to other factors effecting p53 function, such failure to induce downstream regulation of checkpoint proteins or activation via phosphorylation of p53 itself. VAL-083 and cisplatin demonstrate similar effects on p53 induction and activation via phosphorylation and CHK2-related p21 induction in p53 wild-type cisplatin-sensitive (A2780) ovarian cancer cells. However, in cisplatin-resistant (2780CP-16) ovarian cancer cells, only VAL-083 caused significant activation of p53 and p21, and induced greater Ser-15 and Ser-20 phosphorylation of p53, all of which are hallmarks of cytotoxic DNA damage. This further supports the conclusion of distinct modes of action for VAL-083 versus platinum-based chemotherapy and activity against platinum-resistant cancer phenotypes.
Combination of VAL-083 with platinum-based chemotherapy in p53 mutant H1975 NSCLC
The combination of VAL-083 with either cisplatin or oxaliplatin in the human H1975 model demonstrated significant super-additivity (p<0.05) and synergy (CI<1). These results suggest non-overlapping mechanism of action between the platinum drugs and VAL-083, and support the potential for synergistic benefit for a combination of VAL-083 and platinum-based therapies in the treatment of cisplatin resistant cancers.
DelMar Pharmaceuticals, Inc.