Ceralasertib, also identified by its research code AZD6738, is an investigational drug currently undergoing evaluation in oncology. This compound is classified as a targeted cancer therapy, developed by AstraZeneca. It functions as a small-molecule inhibitor, a type of medication designed to interfere with specific molecules involved in cancer growth and progression. Ceralasertib is being studied for its potential in treating various types of cancer, including solid tumors.
Understanding Ceralasertib’s Action
Ceralasertib operates by inhibiting the ataxia telangiectasia and Rad3-related (ATR) protein kinase. ATR is a protein that plays a role in the DNA damage response (DDR) pathway, a system cells use to repair damaged DNA. In normal cells, when DNA damage occurs, ATR is activated, initiating a series of events that temporarily halt the cell cycle, allowing time for DNA repair.
Cancer cells often have high rates of replication and inherent genetic instability, making them particularly reliant on ATR for DNA repair and survival. By inhibiting ATR, ceralasertib disrupts the cancer cell’s ability to repair its DNA, leading to an accumulation of unrepaired DNA damage. This accumulation can overwhelm the cancer cell’s repair mechanisms, ultimately triggering programmed cell death, also known as apoptosis.
This mechanism of action is particularly effective against tumors that have defects in other components of the DDR pathway, such as the ATM (ataxia-telangiectasia mutated) protein or BRCA1/2 genes. ATR inhibition can sensitize tumor cells to chemotherapy and radiotherapy, making them more vulnerable to these standard cancer treatments.
Investigational Uses in Cancer Therapy
Ceralasertib is currently being investigated in clinical trials for various cancer types, often in combination with other established cancer treatments. Clinical studies are exploring its use as a monotherapy and in combination with agents like chemotherapy, radiation, and other targeted therapies.
For example, ceralasertib is being studied in patients with non-small cell lung cancer (NSCLC), where it is being combined with carboplatin, a chemotherapy drug. It is also under investigation for use with durvalumab, an immunotherapy, in patients with squamous cell head and neck cancer, and in those with advanced NSCLC, particularly those with RAS mutations. In gastric cancer, ceralasertib is being explored in combination with durvalumab.
Ovarian cancer is another focus of research for ceralasertib. The drug is being evaluated in combination with olaparib, a PARP inhibitor, to exploit a concept called synthetic lethality. Ceralasertib is also being studied in triple-negative breast cancer, small cell lung cancer, chronic lymphocytic leukemia (CLL), and clear cell gynecologic cancers.
Recognizing Potential Side Effects
As an investigational drug, ceralasertib has been associated with certain side effects observed in clinical trials. The most commonly reported adverse events, particularly with monotherapy and combination treatments, are primarily hematologic, meaning they affect blood cell counts. These include a decrease in the number of blood cells, which can lead to an increased risk of infection, bruising, and bleeding.
Specifically, thrombocytopenia (low platelet count), anemia (low red blood cell count), and neutropenia (low white blood cell count) have been reported as common toxicities. These blood count changes can be dose-limiting toxicities, meaning they can restrict the amount of drug that can be safely given.
Other potential side effects that have been noted include gastrointestinal issues such as feeling or being sick, and inflammation or bleeding from the digestive system. Patients may also experience fatigue, high blood pressure, and increased skin sensitivity to sunlight. Healthcare professionals closely monitor patients for these side effects and manage them through dose modifications or supportive care.
Current Research Landscape
Ceralasertib is currently undergoing various phases of clinical trials to assess its safety and effectiveness as a cancer treatment. These trials typically progress through different phases, starting with Phase I studies to determine the safest dose and identify side effects. Following this, Phase II trials evaluate the drug’s effectiveness in specific cancer types and continue to monitor safety.
Many ongoing studies are Phase I and Phase II, exploring ceralasertib both as a single agent and in combination with other therapies. For instance, a Phase I study investigated ceralasertib combined with carboplatin in patients with advanced solid tumors, establishing a recommended Phase II dose. Another Phase I study explored its combination with weekly paclitaxel in refractory cancer patients, including those with melanoma resistant to prior anti-PD1 therapy.
Phase II trials are also underway for combinations like ceralasertib and durvalumab in advanced gastric cancer and metastatic melanoma. As an investigational agent, ceralasertib has not yet received approval for any indications, but ongoing studies are providing valuable insights into its potential role in cancer therapy.