On May 15, 2020 NuCana plc (NASDAQ:NCNA) reported that two abstracts describing non-clinical studies related to the mechanisms of action of its proprietary ProTides, Acelarin (NUC-1031) and NUC-3373, were selected for poster presentations at the AACR (Free AACR Whitepaper) Annual Meeting 2020 on June 22-24, 2020 (Press release, Nucana BioPharmaceuticals, MAY 15, 2020, View Source [SID1234558115]).

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In prior non-clinical studies, Acelarin has shown an ability to cause cancer-cell death via DNA damage. These new in vitro data presented at AACR (Free AACR Whitepaper) suggest that Acelarin may also have a potential immunomodulatory role. Acelarin was found to cause the release of Damage Associated Molecular Patterns, or DAMPs, and increase the expression of PD-L1 on cancer cells. The findings indicate that Acelarin produces changes in the cancer cells and the tumor microenvironment that could alter the recognition by the immune system, thus potentially making Acelarin an attractive combination partner for immune checkpoint inhibitors.

In the second AACR (Free AACR Whitepaper) abstract, an additional novel mode of action was identified for NUC-3373, NuCana’s ProTide transformation of the active anti-cancer metabolite of 5-fluorouracil (5-FU), a very widely used anti-cancer drug. NUC-3373 was found to be a potent inhibitor of thymidylate synthase, which results in DNA damage of cancer cells. The recent in vitro studies have shown NUC-3373 is able to not only damage DNA, but also induce endoplasmic reticulum stress, and the subsequent release of DAMPs. Thus, in addition to being effective DNA damaging agents in cancer cells, these data suggest that both NUC-3373 and Acelarin may have the potential to alter tumor biology and enhance the activity of immune checkpoint inhibitors.

Hugh S. Griffith, NuCana’s Chief Executive Officer, said: "These findings reveal new and exciting modes of action of our ProTides and help to explain why they appear to be such potent anti-cancer agents."

Acelarin is currently being evaluated in a global Phase III study in combination with cisplatin as a first-line treatment for patients with advanced biliary tract cancer. NUC-3373 is in a Phase Ib clinical study in patients with advanced colorectal cancer in combination with other agents with which 5-FU is typically combined and a Phase I clinical study in patients with advanced solid tumors. NuCana’s third ProTide, NUC-7738, a transformation of a novel nucleoside analog, 3’-deoxyadenosine, is in a Phase I study in patients with advanced solid tumors.

Details of NuCana’s e-poster presentations on June 22-24, 2020: AACR (Free AACR Whitepaper) Virtual Annual Meeting II are as follows:

Abstract Title: NUC-1031 causes release of DAMPs and upregulates PD-L1 expression in lung cancer cells

Poster Number: 1840

Poster Session Title: Mechanisms of Drug Action 2

Abstract Title: NUC-3373 induces ER stress and the release of damage-associated molecular patterns in colorectal cancer cells

Poster Number: 1848

Poster Session Title: Mechanisms of Drug Action 2

Abstracts and full session details can be found at www.aacr.org