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Can PTP1B inhibition rewire macrophage function to improve anti-tumour immunity in breast cancer treatment?


Project Description

Treatment for breast cancer is improving but new therapies are often only successful in a proportion of patients and some patients develop resistance. A key problem is that tumours change the functions of our immune system, so instead of killing cancer cells, signals from the changed immune system helps them grow. Macrophages are the most abundant immune cells in breast cancer and play a fundamental role in driving tumorigenesis through immune suppression, angiogenesis and cancer cell invasion. Tumour-associated macrophages are associated with the aggressiveness of the disease, with a strong clinical correlation between macrophage density and poor prognosis. A high infiltrate of tumour macrophages is associated with a resistance to immune checkpoint inhibitor therapy and chemotherapy.

We are devising ways to switch the function of macrophages, so they eliminate rather than nourish tumours. We will test the hypothesis that PTP1B-inhibitors that have already reached phase 1 clinical trials for breast cancer due to their anti-proliferative effects, can functionally alter the ability of macrophages to destroy tumours. The rationale stems from our published work in other clinical disorders, where PTP1B inhibition significantly changes macrophage functions and favourably alters immune responses to change disease outcome.

This studentship, using human primary macrophages, novel embryonic zebrafish xenograft- and 2D and 3D human mammosphere-preclinical models to define effects of macrophages on immunosuppression, angiogenesis, invasion and signalling pathways, will deliver fundamental information on how to effectively skew macrophage function for increased efficacy of future therapies, using PTP1B inhibition as the switch. You will work in a multidisciplinary team and be trained in cutting edge techniques that will include use of materials derived from a national breast cancer biorepository (www.breastcancertissuebank.org). The project will provide important information to inform future clinical trials as to whether PTP1B-inhibitor therapy, if synergised with other immunotherapeutic strategies, would provide cumulative, more powerful tumour-retarding effects for breast cancer treatment.

APPLICATION PROCEDURE:
Formal applications can be completed online: https://www.abdn.ac.uk/pgap/login.php. You should apply for Degree of Doctor of Philosophy in Medical Sciences, to ensure that your application is passed to the correct person for processing.

NOTE CLEARLY THE NAME OF THE SUPERVISOR AND EXACT PROJECT TITLE ON THE APPLICATION FORM.

Further information on Cancer research at Aberdeen can be found here: https://www.abdn.ac.uk/smmsn/research/cancerabdn-1022.php

Funding Notes

This project is part of a competition funded by the School of Medicine, Medical Sciences and Nutrition for a 4 year PhD programme. Full funding is available to UK/EU candidates only. Overseas candidates can apply for this studentship but will have to find additional funding to cover the difference between overseas and home fees (approximately £15,680 per annum).

Candidates should have (or expect to achieve) a minimum of a 2.1 Honours degree in a relevant subject. Applicants with a minimum of a 2.2 Honours degree may be considered provided they have a Merit/Commendation/Distinction at Masters level.

References

1. Poh AR, Ernst M. Targeting Macrophages in Cancer: From Bench to Bedside. Front Oncol. 2018 Mar 12;8:49.

2. Thompson D, Morrice N, Grant L, Le Sommer S, Lees EK, Mody N, Wilson HM, Delibegovic M. Pharmacological inhibition of protein tyrosine phosphatase 1B protects against atherosclerotic plaque formation in the LDLR-/- mouse model of atherosclerosis. Clin Sci (Lond). 2017 Sep 28;131(20):2489-2501.

3. Kostrzewa T, et al. Inhibitors of Protein Tyrosine Phosphatase PTP1B With Anticancer Potential Anticancer Res. 2019; 7:3379-3384

4. Través PG, Pardo V, Pimentel-Santillana M, González-Rodríguez Á, Mojena M, Rico D, Montenegro Y, Calés C, Martín-Sanz P, Valverde AM, Boscá L. Pivotal role of protein tyrosine phosphatase 1B (PTP1B) in the macrophage response to pro-inflammatory and anti-inflammatory challenge. Cell Death Dis. 2014 Mar 13;5:e112

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