Cancer therapy innovation to overcome traditional limitations

DDW’s Megan Thomas interviews Dr Oren Gilad, President and CEO of Aprea Therapeutics, about the company’s targeted therapeutics that overcome the traditional issues associated with chemotherapy such as toxicity and tumour resistance. MT: Can you provide an overview of Aprea Therapeutics’ approach to developing new cancer therapies and how it differentiates from traditional methods? OG: Aprea is dedicated to improving cancer therapies to overcome the limitations associated with previous anti-cancer treatments, such as toxicity and drug resistance. To achieve this, we focus on targeted therapy which takes advantage of a genetic concept termed synthetic lethality; a defined condition in which combined dysfunction in a pair of genes is lethal to cancer cells, while dysfunction of only one of these genes is not. Essentially, we leverage this genetic concept by developing small molecule inhibitors that are synthetically lethal with cancer-associated genetic mutations. This approach of personalised medicine increases the therapeutic window, making the therapy more effective in killing cancer cells while reducing toxicity to normal non-cancerous tissues. MT: What are the key mechanisms of action for ATRN-119 and APR-1051 and how do they target specific genetic mutations in cancer cells? OG: With ATRN-119, we are targeting a protein called ATR, which is a master regulator of the cell cycle checkpoint response to DNA damage. Cancer cells rely heavily on such checkpoint mechanisms due to their high rate of proliferation. Cancer cells with certain mutations are highly sensitive to inhibition of ATR, a potentially promising example of synthetic lethality. We design our clinical studies to select patients with tumours that harbour these sensitising mutations to ATR inhibition to deliver a targeted therapy that could increase therapeutic responses and is better tolerated by the patients. APR-1051 is a highly selective, and differentiated, inhibitor of WEE1, which regulates two important parts of the cell cycle. Here, we again utilise a synthetic lethal strategy where we select patients based on the cancer-associated genomic alterations that make them sensitive to WEE1 inhibition. Through this personalised approach, APR-1051 could deliver improved overall outcomes for patients. MT: How does ATRN-119’s chemical structure enhance its selectivity and reduce toxicity compared to other ATR inhibitors? OG: To our knowledge, among all the ATR inhibitors that are currently in clinical development, ATRN-119 is the only macrocyclic molecule. Its macrocyclic structure allows it to have increased selectivity by limiting the number of ways it can bind to proteins. This means the molecule can more precisely inhibit ATR and thereby reduce off-target effects. As a result of this more targeted approach, we have the potential to increase the dose to improve efficacy without significantly increasing side effects and toxicity. MT: Can you discuss the rationale behind targeting the DNA damage checkpoint in cancers and how synthetic lethality contributes to this strategy? OG: The DNA damage checkpoint is a quality control mechanism that regulates cell proliferation. As tumours grow, their cells undergo a process of duplication which involves DNA replication. Certain biological processes protect the DNA during the replication stage, and cancer cells rely heavily on these protective processes. This is where synthetic lethality comes into play. We identify specific mutations in cancer cells that increase reliance on ATR or WEE1 and select patients who suffer from cancers that harbour these specific mutations. MT: What are the main challenges and potential advantages of using continuous dosing with ATRN-119 in overcoming tumour resistance? OG: Typically, anti-cancer drugs require patients to be given a break from treatment due to increased toxicity observed with continuous dosing regimens. While these gaps between cycles can help patients recover from side effects, they also enable selection and outgrowth of cancer cells resistant to the current therapy, thus reducing treatment efficacy. ATRN-119 has a safety profile that allows a continuous dosing regimen. Continuous dosing with ATRN-119 can improve overall efficacy and reduce the outgrowth of therapy-resistant cancer cells. Additionally, a continuous dosing regimen generally increases patient compliance due to the easier-to-follow schedule, thus further improving the chances for a positive outcome. MT: In what types of cancers or genetic mutations is APR-1051 showing the most promise, and what preclinical or clinical data supports this? OG: APR-1051 has the potential to be most effective in patients with certain colorectal and uterine cancers with gene mutations that include CCNE1, CCNE2, FBXW7, PPP2R1A, and KRAS and TP53 co-mutation. These mutations render cancer cells more vulnerable to WEE1 inhibition in pre-clinical models, making them good clinical biomarkers for patient selection and treatment with APR-1051. MT: How does APR-1051’s selectivity contribute to its potential as a best-in-class WEE1 inhibitor, and what are the implications for patient outcomes? OG: WEE1 is a clinically validated target, as has been shown in many clinical studies. However, existing WEE1 inhibitors have typically been associated with significant haematological, gastrointestinal, and cardiovascular toxicities. These toxicities are largely related to the off-target effects of the other WEE1 inhibitors in development. APR-1051 is differentiated by its high level of WEE1 selectivity, which allows for the efficient targeting and destruction of cancer cells with minimal off-target effects. Ultimately, we think this will translate into a cancer therapy that is both more effective and safer for patients. This means that patients may have better overall outcomes in addition to a better quality of life during treatment. MT: What are the primary endpoints and key secondary endpoints in the ongoing clinical trials for ATRN-119 and APR-1051? OG: ABOYA-119 is a Phase I/IIa study of ATRN-119 with primary outcome measures to evaluate safety and establish the recommended Phase II dose for ATRN-119. Secondary endpoints include the evaluation of preliminary effectiveness. ACESOT-1051 is a Phase I trial of APR-1051, with primary outcome measures to document the incidence and severity of any adverse events observed during dose escalation. An additional primary outcome is to determine the recommended Phase II dose of APR-1051. Secondary outcome measures include evaluation of preliminary efficacy, pharmacokinetic parameters, plasma concentration over time (AUC), maximum plasma concentration, and time of maximum concentration as well as calculating APR-1051’s half-life. MT: Can you provide a timeline for the upcoming clinical trial phases for ATRN-119 and APR-1051, and what milestones are expected along the way? OG: We are currently enrolling patients in ABOYA-119, a Phase I/IIa open-label study to assess the safety, pharmacokinetics, and preliminary efficacy of ATRN-119 in patients with advanced solid tumours. We expect to complete the dose escalation part of the study during the first half of 2025 followed by dose expansion. We dosed our first patient in June 2024 for ACESOT-1051, a Phase I clinical trial to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of APR-1051. We expect interim data from this study by the end of 2024 and plan to provide safety and preliminary efficacy data during 2025.