AstraZeneca has announced new data from multiple molecules in its industry-leading DNA Damage Response (DDR) pipeline at the 2016 American Association for Cancer Research (AACR) Annual Meeting in New Orleans, LA.
AstraZeneca presents DNA Damage Response science at the AACR 2016 Annual Meeting
- Data from industry-leading DNA Damage Response (DDR) pipeline highlights multiple anti-tumour opportunities in the damage response pathway [1,2,3]
- First-in-class PARP inhibitor Lynparza™ (olaparib) seeks to go beyond ovarian cancer in disrupting single-strand break response [1,4]
- Next-generation investigational Wee1 and ATM inhibitors’ initial data is on cell cycle disruption and double-strand break repair [2,3,5,6]
These agents use a variety of different pathways to disrupt tumour cells’ natural ability to repair themselves as they replicate, eventually causing the tumour cells to die.[7,8] Illustrating the unique breadth of AstraZeneca’s approaches to DDR, presentations at AACR featured molecules that disrupt multiple tumour cell repair processes, including single-strand break repair, double-strand break repair, and cell cycle regulation.[1-6]
Susan Galbraith, Head of AstraZeneca’s Oncology Innovative Medicines Unit said, “Taken together with the positive Phase II results of olaparib in patients with metastatic, castration-resistant prostate cancer published early this year,  we are encouraged by the potential of PARP inhibition in multiple tumour types beyond ovarian cancer. The breadth of our pipeline showcases DDR monotherapies and combinations that could attack cancer in a multitude of novel ways - our first priority, as demonstrated here at AACR, is to follow the science to identify and quickly advance those molecules that have the potential to address the greatest unmet medical needs.”
PARP Inhibition and Lynparza™ (olaparib): Beyond Ovarian Cancer
The PARP inhibitor olaparib is the cornerstone of AstraZeneca’s pipeline of personalised treatments targeting DDR mechanisms in cancer cells. Olaparib was combined with the investigational AKT inhibitor AZD5363 in a new Phase I trial of germline (g) BRCA and non-BRCA mutant (m) advanced cancer patients with ovarian, breast, prostate and bile duct cancers. Results showed that the olaparib-AZD5363 combination was well-tolerated with multiple responses, including 10 RECIST complete or partial responses (out of 37 evaluable patients) in both gBRCA and non-BRCAm tumours, as well as prior PARP inhibitor-treated cancers.
Olaparib disrupts the repair of single-strand DNA breaks, a mode of action that has potential to work in a range of tumour types beyond ovarian cancer.  AstraZeneca is researching how several different compounds can be combined with DDR molecules to provide a dual threat to tumour cells. For example, treatments such as AZD5363 that selectively inhibit the PI3K / AKT signalling pathway may complement olaparib’s interference with tumour DNA repair.
Additional Mechanisms of DDR: Cell Cycle Disruption & Double-Strand Break Repair
AstraZeneca presented data on a variety of investigational compounds acting on different aspects of the DDR pathway, both in monotherapy and in combination. Most significant were early results from a Phase Ib open-label study of AZD1775, a novel small molecule designed to inhibit the Wee1 kinase  Wee1 is a protein kinase that helps regulate the cell cycle 
In many tumours, Wee1 overexpression stops the cell cycle after DNA damage occurs, allowing tumour cells time to repair any damage.[5,11] By inhibiting Wee1, the cell cycle continues despite damage, which can lead to tumour cell death. Assessing the safety, tolerability, pharmacokinetics and anti-tumour activity of AZD1775, the Phase Ib safety run-in included patients with small-cell lung, non-small cell lung, head and neck, ovarian, breast, pancreas and unknown primary tumours. Early results demonstrated a partial or stable response in a third of patients (4/12), and AstraZeneca has initiated expansion cohorts in ovarian, breast and small-cell lung cancer. Other studies currently recruiting include a Phase I multi-centre, dose escalation study of AZD1775 combined with olaparib in refractory solid tumours.
Several other new molecules in the clinical pipeline are entering Phase I development, including the first-in-class Ataxia telangiectasia mutated (ATM) kinase inhibitor AZD0156.3 Pre-clinical in vivo activity of AZD0156 presented at AACR demonstrated that inhibition of ATM during the DNA damage response enhanced the efficacy of a range of DNA-damaging agents, including olaparib, and support its further study in the clinical setting. AstraZeneca is now recruiting for a Phase I trial of AZD0156 as monotherapy or in combination with olaparib in patients with advanced solid tumours.
Other ongoing DDR-focused studies include additional Phase I trials of the Aurora B kinase inhibitor AZD2811  and ATR inhibitor AZD6738 in solid tumours.
About AstraZeneca in Oncology
AstraZeneca has a deep-rooted heritage in Oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With at least 6 new medicines to be launched between 2014 and 2020 and a broad pipeline of small molecules and biologics in development, we are committed to advance New Oncology as one of AstraZeneca’s six Growth Platforms focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy, as illustrated by our investment in Acerta Pharma in haematology.
By harnessing the power of four scientific platforms -- immuno-oncology, the genetic drivers of cancer and resistance, DNA damage response and antibody drug conjugates -- and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.
AstraZeneca is a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of diseases in three main therapy areas - respiratory, inflammation, autoimmune disease (RIA), cardiovascular and metabolic disease (CVMD) and oncology – as well as infection and neuroscience diseases. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information, please visit: www.astrazeneca.com.
1. Michalarea V et al. Phase I trial combining the PARP inhibitor Olaparib (Ola) and AKT inhibitor AZD5363 (AZD) in germline (g)BRCA and non-BRCA mutant (m) advanced cancer patients (pts) incorporating non-invasive monitoring of cancer mutations. AACR 2016 Oral Abstract. Presented April 2016.
2. Bauer T et al. A Phase Ib, Open-Label, Multi-Center Study to Assess the Safety, Tolerability, Pharmacokinetics, and Anti-tumor Activity of AZD1775 Monotherapy in Patients with Advanced Solid Tumors: Initial Findings. AACR 2016 Oral Abstract. Presented April 2016.
3. Thomason A et al. The pre-clinical in vitro and in vivo activity of AZD0156: A first-in-class potent and selective inhibitor of Ataxia telangiectasia mutated (ATM) kinase. AACR 2016 Oral Abstract. Presented April 2016.
4. Swindall A et al. PARP-1: Friend or Foe of DNA Damage and Repair in Tumorigenesis. Cancers 2013, 5, 943-958.
5. Do K et al. Wee1 kinase as a target for cancer therapy. Cell Cycle 12:19, 3159-3164; October 1, 2013.
6. Alvarez-Quilon A et al. ATM specifically mediates repair of double-strand breaks with blocked DNA ends. Nature Communications 5:3347, 27 Feb 2014. 1-10.
7. Krajewska M et al. Regulators of homologous recombination repair as novel targets for cancer treatment. Frontiers in Genetics 6:96 (March 2015).
8. Cheung-Ong et al. DNA-Damaging Agents in Cancer Chemotherapy: Serendipity and Chemical Biology. Chemistry & Biology 20, May 23, 2013. 648-659.
9. Mateo J et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. New England Journal of Medicine 2015;373:1697-708.
10. AstraZeneca. Lynparza Mechanism of Action. Available at https://www.lynparzahcp.com/mechanism-of-action/mechanism-of-action.html. Accessed 11 April 2016.
11. Guertin A et al. Preclinical Evaluation of the WEE1 Inhibitor MK-1775 as Single-Agent Anticancer Therapy. Mol Cancer Ther; 12(8) August 2013: 1442-1452.
12. National Institutes of Health. AZD1775 Combined with Olaparib in Patients with Refractory Solid Tumors. Available at https://clinicaltrials.gov/ct2/show/NCT02511795. Accessed April 2016.
13. National Institutes of Health. A Study to Assess the Safety and Preliminary Efficacy of AZD0156 at Increasing Doses Alone or in Combination with Other Anti-cancer Treatment in Patients with Advanced Cancer (AToM). Available at https://clinicaltrials.gov/ct2/show/NCT02588105?term=AZD0156&rank=1. Accessed April 2016.
14. National Institutes of Health. A Phase I Study of Safety, Tolerability, and PK of AZD2811 in Patients with Advanced Solid Tumors. Available at https://clinicaltrials.gov/ct2/show/NCT02579226?term=AZD2811&rank=1. Accessed April 2016.
15. National Institutes of Health. Phase I Study to Assess Safety of AZD6738 Alone and in Combination With Radiotherapy in Patients With Solid Tumours (Patriot). Available at https://clinicaltrials.gov/ct2/show/NCT02223923. Accessed April 2016.
AstraZeneca is a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of cardiovascular, metabolic, respiratory, inflammation, autoimmune, oncology, infection and neuroscience diseases.