AACR Showcases Breakthroughs in Novel Breast Cancer Diagnosis and Treatment Strategies

The landscape of cancer treatment is rapidly evolving with the emergence of novel therapeutic approaches and innovative technologies. Recent breakthroughs presented at the American Association for Cancer Research (AACR) Annual Meeting 2024 showcase promising advancements in for breast cancer in precision medicine, targeted therapies, and liquid biopsy techniques. From next-generation PARP inhibitors to peptide-conjugate therapies and liquid biopsy platforms, these findings offer new avenues for improving patient outcomes and revolutionizing cancer care.

New PARP Inhibitor Shows Promise in HR-Deficient Breast Cancer 

Saruparib, a novel inhibitor targeting poly-ADP ribose polymerase 1 (PARP1), has emerged as a potential breakthrough in cancer treatment, particularly for patients with certain homologous recombination repair (HRR)-deficient breast cancers. Presented at a press conference for the American Association for Cancer Research (AACR) Annual Meeting 2024, breakthrough findings from the phase I/II PETRA trial showcased Saruparib’s higher selectivity for PARP1, marking a significant advancement in improving safety and tolerability in comparison to existing PARP inhibitors.

Dr. Timothy A. Yap, from The University of Texas MD Anderson Cancer Center, highlighted the crucial distinction of Saruparib being a selective PARP1 inhibitor, unlike current FDA-approved inhibitors that also block PARP2. This singular selectivity potentially reduces toxicity, which effectively allows for higher doses to be administered. It is apparent that dosage and toxicity are a persistent challenge in the development of first-generation PARP inhibitors. 

“When we were developing first-generation PARP inhibitors, we weren’t able to increase the doses above a certain threshold because of toxicity,” Yap said. “By designing selective PARP1 inhibitors, we have a great opportunity to improve safety, tolerability, pharmacokinetics, pharmacodynamics, efficacy, and combinability with other therapies.” 

Saruparib Inhibits Tumor Growth in Multiple Cancers

Saruparib, targeting PARP1 specifically, demonstrated significant tumor growth inhibition in preclinical models of breast, ovarian, pancreatic, and prostate cancer with HRR deficiency mutations. Its lower toxicity allowed for administration at higher doses. According to Dr. Yap, Saruparib’s properties enable patients to maintain high drug exposure and target engagement, potentially improving treatment efficacy by reducing dose interruptions.

PETRA, a phase I/II trial, evaluated Saruparib’s safety, tolerability, and efficacy in 306 patients with HRR-deficient breast, ovarian, pancreatic, or prostate cancer. The recommended dose for further development was determined to be 60 mg daily. Promisingly, in breast cancer patients treated with this dose, an objective response rate of 48.4% and a median progression-free survival of 9.1 months were observed. Importantly, adverse events related to Saruparib were manageable, with a low rate of dose reductions and discontinuations due to side effects. Pharmacokinetic analyses revealed sustained high blood concentrations of Saruparib, ensuring maximal target engagement. Molecular studies showed around 90% inhibition of PARP activity in tumor tissue, indicating effective drug action. The favorable safety profile and sustained target engagement of Saruparib offer promise for long-term benefits in cancer treatment. 

Precise Liquid Biopsy Detects Early Breast Cancer

A platform unveiled groundbreaking breast cancer data at AACR 2024, revealing their RNA- and AI-based liquid biopsy platform’s remarkable sensitivity in detecting stage I breast cancer and ductal carcinoma in situ (DCIS) at 90% specificity. Notably, the platform accurately distinguished low-grade DCIS from invasive breast cancer with 87% sensitivity, offering potential for less aggressive treatment options and improved monitoring for women with DCIS. These findings hint at the transformative potential of a blood test in detecting and managing early-stage breast cancer, potentially offering women an alternative to aggressive or unnecessary treatments.

OncRNA Liquid Biopsy Predicts Survival in TNBC Patients

In a presentation titled “Orphan noncoding RNA (oncRNA) liquid biopsy assay is prognostic for survival in patients with triple-negative breast cancer (TNBC) and residual disease,” recent findings underscore the potential utility of the oncRNA test in predicting which TNBC patients with residual disease may benefit from more intensive treatment.

In a collaboration with the University of Kansas Medical Center, the study showcased a tumor-naive platform’s ability to predict survival in post-adjuvant triple negative breast cancer patients without sequencing tumor tissue. This suggests potential for tailoring adjuvant treatments. The platform employs RNA sequencing to identify cancer-associated small non-coding RNAs, termed oncRNAs, which are stable and abundant in cancer patients’ blood. With an extensive catalog of oncRNAs and patient profiles, combined with AI technology, the platform offers superior sensitivity, specificity, and dynamic tumor biology monitoring capabilities. It can be utilized across various cancer care settings, including screening, monitoring, and therapy selection.

Promising Results from Investigational Peptide-Conjugate Therapies

Preclinical data presented at the AACR meeting, showcased the effectiveness of investigational camptothecin-peptide conjugates in colorectal cancer (CRC) and TNBC xenograft models. These conjugates demonstrated significant tumor regression and good tolerability, suggesting their potential as promising anticancer agents. Moreover, combination therapy with two peptide-drug conjugates showed synergistic anti-tumor effects, resulting in increased tumor growth inhibition and some complete responses in the CRC xenograft model. The observed efficacy of these conjugates, both alone and in combination, highlights their potential in treating various tumor types, including those known for drug resistance.

The scavenger receptor sortilin (SORT1), expressed in various tumor types, facilitates the internalization of anticancer agents into cancer cells. Significantly, SORT1 gene silencing markedly reduced peptide-drug conjugate uptake, confirming a SORT1-mediated internalization process. These findings underscore the potential of peptide-drug conjugates in developing innovative therapies for SORT1-positive tumors, presenting new avenues for cancer treatment.

These promising advancements, including the efficacy of PARP inhibitor Saruparib in HR-deficient breast cancer and its effectiveness across multiple cancer types with reduced toxicity, precise early breast cancer detection, and survival prediction in TNBC via liquid biopsy, alongside the potential therapeutic benefits of investigational peptide-conjugate therapies, collectively signify a hopeful landscape in cancer diagnosis and treatment.

Author

Bernice Lottering