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CLOVES Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Treatment options for CLOVES syndrome and other PIK3CA-related overgrowth disorders include surgical debulking (for truncal lipomatous mass), orthopedic care (for scoliosis/kyphosis and leg-length discrepancy), neurosurgical intervention (for obstructive hydrocephalus, increased intracranial pressure, progressive/symptomatic cerebellar tonsillar ectopia, Chiari malformation, and epilepsy), and other procedures (for cardiac and renal abnormalities; intellectual disabilities, behavior problems, motor difficulties, speech, swallowing, and feeding difficulties). Use of PI3K inhibitor (pictilisib, copanlisib, duvelisib), Akt inhibitor (ipatasertib, MK-2206, ARQ-092), mTOR inhibitor (rapamycin), and dual PI3K/AKT/mTOR inhibitor (gedatolisib, apitolisib) offers another approach for management of PIK3CA-related overgrowth spectrum [25].
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
ATP-competitive inhibitors are the most widely studied agents of this type and work by competing with ATP to occupy the ATP-binding site of the Akt kinase located at the centre of the catalytic domain. Developed by GSK, afuresertib (GSK2110183) is an orally bioavailable potent and selective ATP-competitive pan-Akt kinase inhibitor. It reached Phase II clinical trials for hematologic malignancies including multiple myeloma and CLL; however, no further development has since been reported. The related inhibitor, GSK2141795, also known as uprosertib, differs only in containing a central furan ring rather than a thiophene, along with an additional fluorine atom in the phenyl ring. It reached Phase II clinical trials in multiple myeloma and cervical and prostate cancers but was not further progressed. The AKT inhibitor capivasertib (AZD5363), developed by AstraZeneca, is a pyrrolopyrimidine-derived compound that inhibits all three AKT isoforms. It was evaluated in several Phase II clinical trials in breast, gastric, and prostate cancer, and was progressed to Phase III in combination with paclitaxel or fulvestrant for breast cancer. The combination with fulvestrant afforded good clinical activity in ER+ve/HER+ve breast cancer, and the molecule is still under development. Finally, developed by Array BioPharma and licensed by Genentech, GDC-0068, also known as ipatasertib, is a selective pan-Akt inhibitor active toward all three Akt isoforms. It has been extensively evaluated in the clinic for the treatment of glioblastoma multiforme and ER+ve breast cancer. It is the only ATP-competitive inhibitor in clinical trial with a better selectivity (i.e., 620-fold) for PKB versus PKA. It has reached Phase III clinical trials for the treatment of triple-negative breast cancer, and results to date show that it is well tolerated and clinically active.
Inhibitors of phosphoinositide 3-kinase (PI3K) and phosphoinositide 3-kinase-related protein kinase family (PIKK)
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Xueqin Huang, Li You, Eugenie Nepovimova, Miroslav Psotka, David Malinak, Marian Valko, Ladislav Sivak, Jan Korabecny, Zbynek Heger, Vojtech Adam, Qinghua Wu, Kamil Kuca
Ipatasertib is a highly selective oral ATP-competitive inhibitor that targets all subtypes of AKT285. At present, ipatasertib is mainly developed for the treatment of solid tumours, and a number of clinical trials have been conducted to evaluate its efficacy. The combination of ipatasertib and abiraterone has entered a phase III clinical study in patients with PTEN-deficient mCRPC287. Ipatasertib inhibits PI3K-AKT-mTOR signalling, whereas abiraterone suppresses androgen signalling. The combination therapy increased radiographic PFS by up to 18.5 months286. Patients with TNBC were enrolled in the phase II trial of ipatasertib plus paclitaxel286. When contrasted to the placebo group, the ipatasertib group had a slightly longer median PFS (6.2 months vs. 4.9 months). This was also true in 48 patients with PTEN-low tumours (6.2 months vs. 3.7 months)287. In a nutshell, ipatasertib has surprising potential in the treatment of breast and prostate cancers.
Immune checkpoint inhibition in early-stage triple-negative breast cancer
Published in Expert Review of Anticancer Therapy, 2022
Revati Varma, Matthew Wright, Jame Abraham, Megan Kruse
Beyond investigating immunotherapy with chemotherapy, studies are also exploring the combination of immunotherapy with other pathway inhibitors such as PTEN inhibitors, MAPK inhibitors and anti-hormonal agents. Mutations that result in loss of the PTEN gene occurs in some tumors, leading to constitutive activation of the PI3K/AKT pathway. This upregulation of PI3K pathway induces changes in the tumor microenvironment to become more immune-suppressive [59]. Inhibition of the PI3K/AKT pathway can lead to activation of immune-mediated responses. The phase II BARBICAN trial studied the combination of neoadjuvant NACT and atezolizumab with or without ipatasertib, an AKT inhibitor, in women with high-risk, early-stage TNBC. Patients were randomized to receive one cycle of atezolizumab ± ipatasertib followed by 3 cycles of atezolizumab and 12 weekly paclitaxel treatments ± ipatasertib, followed by 4 cycles of doxorubicin/cyclophosphamide ± ipatasertib. This study found no significant difference in pCR between arms (ipatasertib arm, 49.3%, 95% CI 36.8%–61.8%; control arm, 48.5%, 95% CI 36.2%–61.0%) [60]. Treatment intensity in the ipatasertib arm was low due to toxicity. The future of combination therapies involving immunotherapy and AKT inhibition is uncertain.
Protein kinase inhibitors for the treatment of prostate cancer
Published in Expert Opinion on Pharmacotherapy, 2021
Vincent Chau, Ravi A. Madan, Jeanny B. Aragon-Ching
Of all the agents presented, ipatasertib shows the most potential for further clinical development. Interestingly, ipatasertib only has efficacy in patients who have lost PTEN in both early-phase [73] and late-phase testing [74]. OS and other secondary endpoint data are highly anticipated. In our opinion, this candidate was evaluated in the gold-standard drug-development pathway involving early phase and late phase clinical trials that were designed thoughtfully and rationally. The specific molecular mechanism that explains why patients who have lost PTEN tend to benefit from treatment with ipatasertib remains to be elucidated. It will be exciting to see how this drug candidate fits into the current armament of prostate cancer therapies.