Issue/problem addressed and importance for the society:
Breast cancer remains the second most common cause of cancer death in women in the UK, with around 11,400 deaths annually. Advances in treatment of primary tumours mean that over 85% of patients diagnosed at early stages will survive ≥5 years, but the occurrence of distal metastasis drops 5-year survival rates to <30% for stage IV patients and there is a pressing need for strategies to reduce recurrence of cancer following removal of primary tumours. Although drug-resistant metastasis is a major killer for many types of cancer and remains mostly uncurable, preventative strategies have slowly but steadily improved disease prognosis. Systemic treatment regimens following or preceding surgery (adjuvant or neoadjuvant therapy, respectively) show great promise for prevention of recurrence and metastasis, significantly decreasing mortality rates, particularly for breast cancer. The potential for significant gains for treatments targeting the early metastatic niche is highlighted by the recent success of adjuvant bisphosphonate therapy in breast cancer, which is expected to prevent ≥3 in every 100 deaths of breast cancer annually in the UK.
The main focus of the conducted research project was achieving Rab27a inhibition using novel selective and potent molecules. Rab27 inhibition is most likely to find clinical utility as part of an adjuvant or neoadjuvant treatment regimen in a patient population at significant risk of metastatic recurrence despite standard systemic therapy in the treatment of breast cancer. The initial focus on breast cancer is based on previously obtained preclinical data, significant unmet need, and a feasible clinical development pathway for this unconventional class of agents, but if successful it is likely that Rab27 inhibition could be similarly applied to other solid tumours. The proprietary preliminary data developed in the research group prior my arrival strongly supported the proposal that Rab27a inhibition would enhance the efficacy of adjuvant therapy by targeting the early metastatic niche. There were compelling evidence in models of post-surgery recurrence supporting Rab27a as a valid target in this context.
Overall objectives:
The conducted research had as main focus the development of Rab27a-selective macrocyclic peptide inhibitors with the potential to benefit patient prognosis by offering a novel approach for targeted adjuvant therapy with reduced treatment burden.
Based on preliminary data and extensive in-house assay platform to support development of Rab27a inhibitors, the main objectives for this project were:
1) Identify and develop first in class Rab27a macrocyclic peptide inhibitors;
2) Validate the efficacy of targeting Rab27a with peptide inhibitors using a range of biophysical assays (SPR, thermal shift, FP);
3) Confirm the efficacy of the novel peptide inhibitors in effectively disrupting the Rab27a-effector protein interactions;
4) Evaluate the in cell-permeability of the novel macrocyclic peptide inhibitors;
5) Develop chemical probes to test target engagement in relevant cell-lines.
