AZD4547 is an investigational medication designed to interfere with specific pathways within cancer cells that contribute to their uncontrolled growth. This targeted therapy aims for precise treatment by focusing on a tumor’s molecular characteristics. It is currently undergoing clinical investigation to evaluate its effectiveness and safety.
The Role of FGFRs in Cancer
Fibroblast Growth Factor Receptors (FGFRs) are a family of proteins on the surface of cells that regulate normal cell processes. They act like receivers, picking up signals from fibroblast growth factors (FGFs). These signals regulate cellular activities like growth, division, and repair in development and adult tissues.
Normally, FGFRs maintain healthy tissue development and regeneration. However, alterations or mutations in FGFRs can disrupt this balance, leading to uncontrolled cell proliferation and survival. This dysregulation can contribute to cancer development and progression. Increased FGFR signaling can promote tumor growth, angiogenesis (new blood vessel formation that feeds tumors), and resistance to other cancer treatments.
How AZD4547 Works as an Inhibitor
AZD4547 is a selective inhibitor, designed to specifically target components of the fibroblast growth factor receptor (FGFR) family. It primarily focuses on FGFR1, FGFR2, and FGFR3, with weaker activity against FGFR4. This selectivity helps minimize off-target effects, aiming for precise therapeutic action.
The drug works by inhibiting the tyrosine kinase activity of these FGFRs. Tyrosine kinases are enzymes that activate signaling pathways inside the cell. By blocking this activity, AZD4547 interferes with signals promoting tumor cell growth and survival. This disruption suppresses cancer cell proliferation and reduces tumor signaling, effectively slowing or stopping tumor progression.
Current Research and Clinical Applications
AZD4547 is under clinical investigation for various FGFR-dependent tumors, including lung, gastric, bladder, and breast cancers, where FGFR aberrations are frequently observed. Preclinical studies demonstrated AZD4547 can inhibit tumor growth in models with deregulated FGFRs, providing a basis for clinical evaluation.
Clinical trials evaluated AZD4547’s efficacy and safety in patients with solid tumors harboring FGFR abnormalities. In a phase II study, patients with FGFR1-3 aberrations received AZD4547 at 80 mg orally twice daily. This trial observed confirmed partial responses in 8% of patients and stable disease in 37.5%. Responses were primarily seen in tumors with FGFR activating mutations and fusions.
For patients with FGFR fusions, the response rate was 22%, and the 6-month progression-free survival rate was 56%. While AZD4547 did not meet its primary endpoint in this particular trial for all FGFR aberrations, these findings suggest potential activity in specific genetic subgroups. Other studies have investigated AZD4547 in FGFR1-amplified squamous cell lung cancer and FGFR2-amplified gastric cancer. In patients with FGFR2-amplified gastric cancer, three out of nine patients demonstrated a long-term response.
The Future of FGFR Inhibition
The ongoing research into AZD4547 and other FGFR inhibitors highlights a growing focus on precision medicine in cancer treatment. A significant aspect of this approach is patient selection, which involves identifying individuals whose tumors have specific FGFR aberrations that are likely to respond to the drug. This often relies on advanced molecular testing of tumor tissue to detect gene amplifications, mutations, or fusions in FGFRs.
The development of companion diagnostics plays a part in this process, as these tests help determine which patients are most likely to benefit from a particular targeted therapy. For instance, some FDA-approved FGFR inhibitors utilize gene fusions and mutations as companion diagnostics for patient selection. Ongoing research continues to explore combination therapies, where FGFR inhibitors might be used alongside other treatments to enhance effectiveness or overcome resistance, potentially broadening the impact of these targeted approaches in the evolving landscape of cancer care.