Saracatinib, an investigational drug developed by AstraZeneca, was once a compound of interest in oncology. It was designed as a targeted therapy to interfere with specific molecules involved in cancer cell growth. Despite promising laboratory results, its development was halted after it failed to demonstrate sufficient effectiveness in human trials. This outcome led to its discontinuation for cancer, though research into other potential uses for the drug has continued.
The Intended Purpose of Saracatinib
Saracatinib was engineered as a Src kinase inhibitor. Src kinases are a family of enzymes that act as messengers within cells, transmitting signals that control fundamental processes like cell division, movement, and survival. In many types of cancer, these signaling pathways become overactive, contributing to the uncontrolled growth and spread of tumors. By blocking Src kinases, saracatinib was intended to interrupt these overactive signals and slow tumor progression.
The drug works by competitively binding to the ATP-binding site on the kinase, preventing it from functioning. This mechanism showed potential against several cancer types where Src signaling is a known factor. AstraZeneca investigated saracatinib in cancers including ovarian, prostate, breast, and bone cancer. The goal was to offer a new treatment option for these difficult-to-treat diseases.
Laboratory studies and animal models indicated that saracatinib could inhibit the signaling pathways associated with tumor invasion and metastasis. These promising early findings provided the scientific rationale for advancing the drug into clinical trials.
Clinical Trials and Reasons for Discontinuation
The primary reason for discontinuing saracatinib was its lack of significant efficacy in phase II clinical trials. While generally well-tolerated, the drug failed to meet its primary endpoints for various cancers, including metastatic breast and colorectal cancer. It did not demonstrate a meaningful improvement in patient outcomes compared to existing treatments or a placebo.
For instance, a phase II study on patients with previously treated metastatic colorectal cancer found that saracatinib did not improve progression-free survival. Similarly, in a trial for patients with hormone receptor-negative metastatic breast cancer, no patients achieved a complete or partial response. The majority of participants discontinued treatment due to disease progression.
The decision was based on insufficient therapeutic action rather than major safety issues, although some adverse events were reported. Common side effects included fatigue, nausea, and elevated liver enzymes. In rare cases, more serious events like pulmonary toxicity were observed.
The Current Landscape for Src Kinase Inhibitors
The discontinuation of saracatinib did not end research into Src kinase inhibitors as a class of drugs, as the Src kinase family is still considered a valid target in oncology. Other drugs that inhibit Src kinases have found success in different contexts. For example, dasatinib, which also inhibits Src family kinases, is an approved treatment for certain types of leukemia.
This demonstrates that the effectiveness of a kinase inhibitor can be highly dependent on the specific cancer type and its genetic makeup. While saracatinib was not successful for solid tumors like breast or colorectal cancer, the broader strategy of targeting Src signaling remains an active area of research. Scientists continue to explore new compounds and combination therapies aimed at this target.
For the cancers that saracatinib was intended to treat, such as ovarian and non-small cell lung cancer, standard-of-care has continued to evolve. Treatment regimens for these diseases typically involve a combination of surgery, radiation, chemotherapy, and other targeted therapies. These are tailored to the specific characteristics of a patient’s tumor.