From the Guidelines
Yes, there are targeted therapies for PTEN mutations, primarily focusing on the PI3K/AKT/mTOR pathway that PTEN normally regulates. The most recent and highest quality study 1 suggests that PTEN mutations are common in endometrial cancer, and targeting the PI3K/AKT/mTOR pathway can be an effective treatment approach.
Key Points:
- The PI3K/AKT/mTOR pathway is one of the most frequently altered signaling pathways in endometrioid tumors, often resulting from mutations in PTEN, PIK3CA, and PIK3RI.
- mTOR inhibitors such as everolimus and temsirolimus are established treatments for PTEN mutations, and work by blocking mTOR, which becomes overactivated when PTEN is mutated.
- Newer targeted approaches include dual PI3K/mTOR inhibitors like gedatolisib and AKT inhibitors such as capivasertib, though many remain in clinical trials.
- Genetic testing should confirm the specific PTEN mutation, as response varies based on mutation type and cancer context.
- Side effects of mTOR inhibitors typically include stomatitis, rash, fatigue, and metabolic changes requiring monitoring.
Treatment Considerations:
- PTEN mutations drive cancer growth by removing the natural brake on the PI3K/AKT/mTOR pathway, which controls cell growth and survival.
- Targeted therapies can be effective, but are often used as part of combination regimens with other treatments to prevent resistance mechanisms from developing.
- The TCGA Research Network has performed an integrated genomic characterization of endometrial carcinoma, which has identified potential targets for therapy, including the PI3K/AKT/mTOR pathway 1.
- The PRoMise molecular classifier has recently been validated in a larger, population-based case series with good results, and can be used to categorize tumors into one of four groups analogous to those described in TCGA analyses 1.
From the Research
Targeted Therapies for PTEN Mutation
There are several targeted therapies being developed and investigated for the treatment of cancers with Phosphatase and Tensin Homolog (PTEN) mutation. Some of these therapies include:
- AKT inhibitors, such as TAS-117, which have shown promise in treating advanced solid tumors with germline PTEN-inactivating mutations 2
- PI3K/AKT/mTOR inhibitors, which have been shown to be effective in treating a variety of hematologic malignancies and solid tumors 3
- Combination therapies, which have been shown to be more effective than single-agent therapies in treating cancers with PTEN mutations 3, 4
Mechanism of Action
The mechanism of action of these targeted therapies involves inhibiting the PI3K/AKT/mTOR pathway, which is often upregulated in cancers with PTEN mutations. This pathway is involved in cell growth, survival, and proliferation, and its inhibition can lead to the death of cancer cells. For example, the novel allosteric AKT inhibitor TAS-117 has been shown to have activity against certain tumor types 2.
Clinical Trials and Studies
Several clinical trials and studies have been conducted to investigate the safety and efficacy of these targeted therapies in treating cancers with PTEN mutations. For example, a phase II study of TAS-117 in patients with advanced solid tumors harboring germline PTEN-inactivating mutations is currently underway 2. Another study found that PI3K/AKT/mTOR inhibitors achieved tumor response in 5.3%, 2.8%, and 31% of patients when given as monotherapy, respectively 4.
Potential Benefits and Challenges
The potential benefits of these targeted therapies include improved treatment outcomes and increased survival rates for patients with cancers with PTEN mutations. However, there are also challenges involved in treating patients with PTEN-deficient cancers, including the development of resistance to these therapies 5. Further clinical trials and studies are needed to fully investigate the safety and efficacy of these targeted therapies and to overcome the challenges involved in treating patients with PTEN-deficient cancers.