Oral Presentation Clinical Oncology Society of Australia Annual Scientific Meeting 2022

Angiotensin receptor 1 blockade blocks cancer-induced memory impairment in a mouse model of breast cancer. (#54)

Yasmine Kostoglou 1 , Alan Tao 1 , Delyse McCaffrey 2 , Raymond J Chan 3 , Janette L Vardy 4 , Teri Furlong 5 , Adam J Lawther 1 , Adam K Walker 1 6 7
  1. Laboratory of ImmunoPsychiatry, Neuroscience Research Australia, Randwick, NSW, Australia
  2. Neuroscience Research Australia, RANDWICK, NSW, Australia
  3. Caring Futures Institute, Flinders University, Adelaide, SA, Australia
  4. Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
  5. School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
  6. Discipline of Psychiatry and Mental Health, University of New South Wales, Sydney, NSW, Australia
  7. Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia

Background: Despite cognitive impairment being common in cancer patients, no treatment exists. Recent clinical evidence implicates the renin-angiotensin system (RAS) in the pathophysiology of cancer-related cognitive impairment (CRCI), however whether the RAS plays a causal role in CRCI remains unknown. In the brain, angiotensin receptor (ATR)1 signalling is associated with cognitive impairment, whereas ATR2 signalling promotes brain health and cognition. Using a mouse model of breast cancer, we investigated if a peripheral tumour impacts brain RAS gene expression and memory impairment, and if the ATR1 antagonist, candesartan, reduces tumour-induced memory impairment.

Methods: 48 female Balb/c mice bearing 4T1.2 mammary tumours or non-tumour bearing mice were treated with candesartan (3mg/kg, IP) or vehicle daily, and assessed for memory using the novel object/novel place recognition task. Brain region-specific changes in RAS gene expression were quantified using qRT-PCR. Because RAS activation can enhance blood-brain barrier (BBB) leakiness, we also assessed blood-to-brain fluorescein diffusion.

Results: Mammary tumours induced spatial reference memory impairment, which was prevented by treatment with candesartan (p<0.05). Tumours reduced hippocampal expression of ATR1 (p<0.05) and ATR2 (p=0.07). Candesartan increased cortical angiotensin-converting enzyme (ACE) expression, which produces the ligand for ATRs, and significantly enhanced cortical BBB integrity (p<0.05). Candesartan had no effect on cancer progression, or sickness responses, supporting its safety for use in cancer patients.

Conclusions: The findings demonstrate that that a solid peripheral tumour can induce changes in brain RAS gene expression and memory impairment, which is prevented by ATR1 antagonists. Antagonism of the ATR1 and increased production capacity of angiotensin II may improve cognition by shifting angiotensin signalling toward the pro-cognitive ATR2 pathway. Another possibility is that reducing BBB permeability is sufficient to block cancer-induced memory impairment.  The findings suggest that candesartan may be a safe and effective treatment for cancer-induced memory impairment, supporting its advancement to clinical trials.