Periodic Reporting for period 1 - RabTarget4Metastasis (Targeting Rab27A with covalent inhibitors for the treatment of metastatic breast cancer)
Reporting period: 2020-08-01 to 2022-07-31
The project entitled “Targeting Rab27A with covalent inhibitors for the treatment of metastatic breast cancer” aimed at investigating a novel approach in the treatment and prevention of breast cancer metastasis. Spreading of the primary tumour to secondary distal sites, i.e. the metastatic process, is the leading cause of cancer death worldwide and unfortunately remains mostly untreatable. Fundamental research such as the one supported by this action is therefore pivotal to help overcome current healthcare barriers and ultimately it will impact patients’ life and enhance treatment options.
This innovative line of research envisioned the validation of a promising therapeutic target, namely the small guanosine triphosphatase (GTPase) protein Rab27A. Recent studies have shown a clear role for Rab27A in supporting the process of tumour migration and invasion. Small GTPases are notoriously challenging targets for small molecule drug discovery. For this reason, we planned to inhibit Rab27A via covalent drugs, which have several advantages and have shown unprecedent potential to address historically challenging targets such as GTPases, as best exemplified by the recently approved Sotorasib, the first clinical inhibitor of a Ras GTPase.
Following promising preliminary results for this work, the following aims were established (as described in detail in the MSCA-IF proposal):
1. Obtaining specific and potent covalent Rab27A inhibitors;
2. Demonstrating engagement of Rab27A in cells and effective inhibition in vitro;
3. Optimising the best compounds for progression towards in vivo models for clinical translatability.
The final report will summarise the main milestones of the project, its current status and further outlook, including tangible output and dissemination activities. In line with project aims, leading a team of 2–4 chemists within the Tate group, we have developed the first chemical probes that engage native Rab27A in cells. Our results will be pivotal to demonstrate the potential of targeting Rab27A as a therapeutic strategy to prevent and combat tumour metastasis. Furthermore, the action has enabled the development of the fellow’s profile for progression into competitive, internationally leading research roles.
This innovative line of research envisioned the validation of a promising therapeutic target, namely the small guanosine triphosphatase (GTPase) protein Rab27A. Recent studies have shown a clear role for Rab27A in supporting the process of tumour migration and invasion. Small GTPases are notoriously challenging targets for small molecule drug discovery. For this reason, we planned to inhibit Rab27A via covalent drugs, which have several advantages and have shown unprecedent potential to address historically challenging targets such as GTPases, as best exemplified by the recently approved Sotorasib, the first clinical inhibitor of a Ras GTPase.
Following promising preliminary results for this work, the following aims were established (as described in detail in the MSCA-IF proposal):
1. Obtaining specific and potent covalent Rab27A inhibitors;
2. Demonstrating engagement of Rab27A in cells and effective inhibition in vitro;
3. Optimising the best compounds for progression towards in vivo models for clinical translatability.
The final report will summarise the main milestones of the project, its current status and further outlook, including tangible output and dissemination activities. In line with project aims, leading a team of 2–4 chemists within the Tate group, we have developed the first chemical probes that engage native Rab27A in cells. Our results will be pivotal to demonstrate the potential of targeting Rab27A as a therapeutic strategy to prevent and combat tumour metastasis. Furthermore, the action has enabled the development of the fellow’s profile for progression into competitive, internationally leading research roles.
The work plan was divided into 3 main work packages (WPs) tailored to the achievement of the proposed project goals: WP1 entailed different strategies to accelerate the medicinal chemistry campaign to optimise the novel compounds; WP2 aimed at testing the best inhibitors to prove their efficacy in biochemical assays and cellular models; WP3 envisioned the refinement of the best candidates’ properties for advancement into preclinical studies.
WP1 and WP2 were conducted in parallel, leading to major breakthroughs for the project, partly included in a peer reviewed article, and the generation of intellectual property which is currently undergoing patenting processes and will be then also published in high impact scientific journals. The work was also presented at international conferences where important collaborations have been engaged. Further output from collaborative efforts of the fellow’s work at the host lab has resulted overall in an additional 6 peer reviewed publications and 1 book chapter. WP3 is conducted partly in collaboration with the Norman group at CRUK Beatson and is currently still ongoing.
In addition to meeting scientific goals, the fellow has engaged in a number of outreaching activities, including a very popular stand on innovative therapies at the Great Exhibition Road Festival 2022. These endeavours aimed at reaching the general public and spreading understanding on the importance of discovery research for the general advancement of science.
Despite delays due to reduced lab access caused by pandemic COVID-19, the MSCA-IF goals, including the development of the fellow and the significant advancement of this ambitious research project can be considered well met and have generated further seeds for the continuation and enhancement of this work (e.g. recognition of the fellow by the L’Oréal-UNESCO UK For Women in Science 2022, Award of a Worldwide Cancer Research grant with the fellow listed as co-investigator).
WP1 and WP2 were conducted in parallel, leading to major breakthroughs for the project, partly included in a peer reviewed article, and the generation of intellectual property which is currently undergoing patenting processes and will be then also published in high impact scientific journals. The work was also presented at international conferences where important collaborations have been engaged. Further output from collaborative efforts of the fellow’s work at the host lab has resulted overall in an additional 6 peer reviewed publications and 1 book chapter. WP3 is conducted partly in collaboration with the Norman group at CRUK Beatson and is currently still ongoing.
In addition to meeting scientific goals, the fellow has engaged in a number of outreaching activities, including a very popular stand on innovative therapies at the Great Exhibition Road Festival 2022. These endeavours aimed at reaching the general public and spreading understanding on the importance of discovery research for the general advancement of science.
Despite delays due to reduced lab access caused by pandemic COVID-19, the MSCA-IF goals, including the development of the fellow and the significant advancement of this ambitious research project can be considered well met and have generated further seeds for the continuation and enhancement of this work (e.g. recognition of the fellow by the L’Oréal-UNESCO UK For Women in Science 2022, Award of a Worldwide Cancer Research grant with the fellow listed as co-investigator).
Considering the lack of good chemical probes to study Rab27A as a potential target for metastatic breast cancer, this MSCA has significantly advanced our capabilities to evaluate the therapeutic potential of this novel approach. Furthermore, the fellow’s dissemination and research activity in the field of covalent drug discovery has significantly impacted the representation of women in this area of research, as recognised also by the L’Oréal-UNESCO UK For Women in Science nomination (2022) and by further engagement in renowned panels (e.g. the fellow was interviewed by C&EN among experts in the field (The Future of Covalent Drugs, Discovery Report Q3, C&EN, 2022)).
The potential of the intellectual property generated by this work is currently under evaluation and will result in a patent covering the novel compounds, after which the results will also be disseminated in peer reviewed journals and international conferences (expected impact within 2 years from the end of the action).
Finally, the action has significantly enhanced the fellow’s profile providing her with the required competitiveness and skills, both practical and soft ones, including substantial mentoring experience. This has empowered the fellow to independently advance scientific research at the interface of chemistry and biology. This will enable a career in academia or industry within Europe, with a renewed commitment to train future scientists.
The potential of the intellectual property generated by this work is currently under evaluation and will result in a patent covering the novel compounds, after which the results will also be disseminated in peer reviewed journals and international conferences (expected impact within 2 years from the end of the action).
Finally, the action has significantly enhanced the fellow’s profile providing her with the required competitiveness and skills, both practical and soft ones, including substantial mentoring experience. This has empowered the fellow to independently advance scientific research at the interface of chemistry and biology. This will enable a career in academia or industry within Europe, with a renewed commitment to train future scientists.