From the Guidelines
The treatment approach for Akt-related conditions, given the non-recognition of Akt4 in human medicine, involves targeting the PI3K/Akt pathway with inhibitors such as everolimus, an oral mTOR inhibitor, which has shown effectiveness in clinical trials for conditions like Waldenström's macroglobulinemia (WM) with an overall response rate (ORR) of 72% and 73% in newly diagnosed and relapsed/refractory patients, respectively 1.
Key Considerations
- The established Akt family consists of three isoforms (Akt1, Akt2, and Akt3), and thus, any treatment approach for "Akt4" would actually be aimed at these recognized isoforms.
- Everolimus, as an example of an mTOR inhibitor, is administered orally until disease progression or unacceptable toxicity, with common side effects including anemia, rash, oral ulcerations, and neutropenia 1.
- Another agent, perifosine, an inhibitor of Akt, has shown antitumor activity in preclinical and clinical studies of WM, although it is not currently endorsed by treatment guidelines, with an ORR of 35% in relapsed and/or refractory WM patients 1.
Treatment Approach
- For conditions where the Akt pathway is implicated, such as certain cancers, the use of PI3K/Akt pathway inhibitors is being explored.
- The choice of inhibitor and dosage would depend on the specific condition, the stage of the disease, and the patient's overall health status.
- Monitoring for side effects such as gastrointestinal disorders, fatigue, and cytopenias is crucial during treatment with these inhibitors.
Rationale
- The Akt pathway plays a critical role in cell survival, proliferation, and metabolism, and its dysregulation is associated with various diseases, including cancer.
- Inhibiting this pathway can help restore normal cellular function and induce cell death in cancer cells, making it a promising therapeutic strategy.
From the FDA Drug Label
The efficacy of TRUQAP with fulvestrant was evaluated in CAPItello-291 (NCT04305496), a randomized, double-blind, placebo-controlled, multicenter trial that enrolled 708 adult patients with locally advanced (inoperable) or metastatic HR-positive, HER2-negative (defined as IHC 0 or 1+, or IHC 2+/ISH-) breast cancer of which 289 patients had tumors with eligible PIK3CA/AKT1/PTEN-alterations.
The treatment approach for Akt 4 (Protein Kinase B 4) related conditions, specifically in the context of PIK3CA/AKT1/PTEN-altered tumors, involves the use of TRUQAP (capivasertib) in combination with fulvestrant. This combination has shown a statistically significant difference in progression-free survival (PFS) in patients with PIK3CA/AKT1/PTEN-altered tumors 2.
- Key points:
- TRUQAP is administered orally at a dose of 400 mg twice daily for 4 days, followed by 3 days off treatment, in a 28-day treatment cycle.
- Fulvestrant is administered as an intramuscular injection of 500 mg on cycle 1 days 1 and 15, and then at day 1 of each subsequent 28-day cycle.
- Patients are treated until disease progression or unacceptable toxicity. The FDA drug label does not provide information on the treatment of Akt 4 specifically, but rather on the treatment of PIK3CA/AKT1/PTEN-altered tumors.
From the Research
Treatment Approach for Akt 4 Related Conditions
The treatment approach for Akt 4 (Protein Kinase B 4) related conditions involves targeting the PI3K/AKT/mTOR signaling pathway, which is frequently dysregulated in various cancers.
- The PI3K/AKT/mTOR pathway plays a critical role in cell growth and survival, and its dysregulation has been found in a variety of cancer cells 3.
- Inhibitors of this pathway, such as MK-2206 and perifosine, have shown promising results in sensitizing cancer cells to therapy in vitro and in vivo 4.
- However, despite the acceptable safety profile of some of these agents in clinical studies, the results are still too preliminary, and more data is needed from ongoing trials before they can be incorporated into standard care 4.
Current Therapies and Resistance
Current therapies targeting the PI3K/AKT/mTOR pathway include everolimus (mTOR inhibitor), alpelisib (PIK3CA inhibitor), and capivasertib (AKT inhibitor) 5.
- Resistance to these therapies is a major problem in the clinical setting, and can be categorized into intrinsic or acquired resistance depending on the timeframe it develops within 5.
- The majority of patients with ER-positive, HER2-negative advanced breast cancer will likely develop resistance to these therapies at some point, making it an area of interest and an unmet need 5.
Emerging Paradigms for Targeted Cancer Therapy
Inhibition of PI3K/Akt signaling has emerged as a promising paradigm for targeted cancer therapy 3.
- Ipatasertib, an oral AKT inhibitor, has shown promising data in solid tumors, including serous endometrial cancer, by inhibiting cell proliferation and migration, and inducing apoptosis 6.
- Combination therapy with ipatasertib and paclitaxel has also shown synergistic effects in reducing cell proliferation and increasing apoptosis in serous endometrial cancer cells 6.
Future Directions
Further studies are needed to explore the functional impact of AKT inhibitors on anti-tumorigenic activity in various cancer types, including breast cancer and serous endometrial cancer 5, 6.
- The development of novel AKT inhibitors with high selectivity, bioavailability, and potency is also needed to overcome resistance and improve treatment outcomes 3.