Dual Epithelial and Stromal Targeting in Breast Cancer Using the Phase II ROCK2 Inhibitor KD025 Guided by Intravital Imaging Technology
Abstract
Rationale, Objectives, and Aims: Tissue fibrosis is a well-known risk factor for breast cancer (BC) initiation, progression, and prognosis. It is commonly found in aggressive cancers, such as the triple negative breast cancer (TNBC) subtype. Fibrosis is also known to protect cancer cells from treatment including chemotherapy, which is the standard-of-care in TNBC. We have acquired the novel drug KD025, a highly specific and clinically relevant ROCK2 inhibitor (currently under phase 2 assessment to treat fibrosis in skin and lung diseases), and our preliminary experiments show it to be an excellent candidate to impair tissue fibrosis in TNBC. In this proposal we will test the hypothesis that KD025 can reduce tissue fibrosis and improve standard-of-care chemotherapy performance in preclinical models of TNBC. Our specific aims are to: Aim 1: Optimize anti-fibrotic KD025 treatment to improve standard-of-care chemotherapy Aim 2: Assess survival outcomes of KD025 combined with chemotherapy in a genetically engineered mouse model of TNBC Aim 3: Deliver personalized combination therapy to highly fibrotic patient-derived tumors, which have been matched to our approach and are most likely to respond (precision medicine approach) Methodology: Our laboratories have set up a unique approach to accurately model TNBC in a preclinical context. We use microscopy to directly visualize and optimize therapeutic response in live animal and patient-derived BC. Here, we will use our expertise to accelerate the re-purposing of anti-fibrotic KD025 treatment to TNBC. Importantly, our contribution to the understanding of anti-fibrotic therapy will also be pivotal for the treatment of other cancer types that are characterized by extensive tissue fibrosis. Overarching Challenges: KD025 is currently already used in humans under phase 2 clinical investigation for skin and lung diseases to treat tissue fibrosis (NCT03919799, NCT02688647) and could be rapidly re-purposed to BC treatment to Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival. Fibrosis has also been shown to enhance cancer spread to secondary sites and we therefore expect that anti-fibrotic KD025 treatment will also significantly impair or delay TNBC metastasis to Eliminate the mortality associated with metastatic breast cancer. If successful, the results from this project could provide preclinical efficacy data to inform the rapid re-purposing of KD025 (already in-human, phase 2) for combination with standard-of-care chemotherapy in TNBC. The short-term outcome of this study (within 3 years) will be to establish whether KD025, a phase 2 clinical drug that is safe to use in humans, can impair tissue fibrosis and improve standard-of-care chemotherapy in TNBC. We can then commence window-of-opportunity clinical trials to quickly evaluate efficacy of this new therapy in the clinical setting. These studies consist of neoadjuvant treatments (between diagnosis and surgery) of usually 2 to 4 weeks that readily gives information about treatment response. This type of trial is regularly run on-site and our in-house Clinical Trials Centre at The Kinghorn Cancer Centre (TKCC) is optimally set up to support these trials through a close integration of patient treatment and research. In collaboration with our Anatomical Pathology leader, we also aim to develop a way to stratify patients by finding out how much of the target protein (ROCK2) they express and determining the level of fibrosis for each patient. This will allow us to choose patients who are most suitable for the window-of-opportunity trial. In the medium term of 3 to 8 years, if our window-of-opportunity trial is successful, we will test our drug combination in larger-scale clinical trials across advanced TNBC cases. A potential barrier to our success is the difficulty in raising funds and recruiting patients to participate in clinical
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210104
Entities
People
- Paul Timpson
Organizations
- Garvan Institute of Medical Research
- United States Army