Rigosertib is an investigational drug that has been studied for its potential in treating certain types of cancer. This article aims to provide a general overview of rigosertib, detailing its mechanism of action, its progress through clinical development, and reported side effects for a broad audience.
Understanding Rigosertib
Rigosertib is classified as a small molecule inhibitor, specifically a synthetic benzyl styryl sulfone analogue. It is also known as a Ras mimetic. This drug has been investigated for various cancer types, with a primary focus on myelodysplastic syndromes (MDS), particularly high-risk MDS, and metastatic pancreatic cancer.
The drug’s design allows it to interfere with specific cellular processes that are often overactive in cancer cells. Rigosertib targets key signaling pathways, including phosphoinositide 3-kinase (PI3K) and Polo-like kinase 1 (PLK1). It functions by disrupting the normal communication networks within cancer cells, thereby impeding their uncontrolled growth.
How Rigosertib Works
Rigosertib exerts its effects by interfering with several critical pathways involved in cancer cell proliferation and survival. It was initially described as an inhibitor of Polo-like kinase 1 (PLK1), a protein that plays a significant role in regulating cell division. By inhibiting PLK1, rigosertib can cause cancer cells to halt their division and undergo programmed cell death.
Beyond PLK1, rigosertib also acts as a Ras mimetic. This means it can bind to specific regions, known as Ras-binding domains (RBDs), on proteins that interact with Ras, a crucial signaling molecule often mutated in cancer. By occupying these binding sites, rigosertib prevents Ras from activating downstream pathways like Ras/Raf/Erk and PI3K/Akt. This disruption leads to cell cycle arrest at the G2/M phase and subsequent apoptosis in cancer cells. The drug has demonstrated selective toxicity, largely affecting cancer cells while having minimal impact on normal, healthy cells at therapeutic concentrations.
Clinical Journey and Current Status
Rigosertib has progressed through various stages of clinical development. Early Phase 1 trials indicated that the drug was generally well-tolerated by patients, with some individuals experiencing stable disease.
In the treatment of myelodysplastic syndromes (MDS), rigosertib underwent a significant Phase 3 trial called ONTIME. This study compared intravenous rigosertib plus best supportive care against best supportive care alone in high-risk MDS patients who had previously failed hypomethylating drugs. While the trial did not meet its primary goal of statistically significant improvement in overall survival for the entire study population, a subgroup analysis suggested a potential benefit in patients who had not responded to prior hypomethylating agent treatment.
A subsequent Phase 3 trial, INSPIRE, designed based on these subgroup findings, also did not show a statistically significant improvement in overall survival for higher-risk MDS patients who had failed prior treatments. Currently, oral rigosertib is being investigated in Phase 1/2 trials in combination with azacitidine for higher-risk MDS. The orphan drug designation for rigosertib in MDS was withdrawn in 2021.
For pancreatic cancer, rigosertib was evaluated in the Phase 3 ONTRAC trial, combining it with gemcitabine as a first-line treatment for metastatic disease. This trial was discontinued after an interim analysis determined it was unlikely to achieve its primary endpoint of improving overall survival compared to gemcitabine alone. Despite these outcomes, rigosertib continues to be explored in other areas, including Phase 2 studies for squamous cell carcinoma.
Reported Side Effects
Clinical trials of rigosertib have documented a range of potential side effects experienced by patients. Common adverse reactions have included fatigue, diarrhea, nausea, constipation, and anorexia. Some patients also reported dysuria, which is painful urination, and hematuria, or blood in the urine.
More severe side effects, classified as Grade 3 or 4, observed in studies have included hematologic issues such as anemia, thrombocytopenia, and neutropenia, as well as febrile neutropenia. Other significant adverse events included pneumonia, muscular weakness, hyponatremia, delirium, and confusional states. While these side effects were reported, the drug was generally considered well tolerated in many clinical studies.