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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Perifosine (KRX-0401) inhibits both PI3K and AKT, and was developed by Keryx Biopharmaceuticals for a variety of cancer indications. It has an alkyl-phospholipid structure related to miltefosine. Perifosine reached Phase II clinical trials for metastatic colon cancer in 2010, and was assigned Orphan Drug status by the FDA for the treatment of multiple myeloma and neuroblastoma (and for multiple myeloma by the EU). However, it failed to reach its anticipated clinical endpoints in a Phase III clinical trial in colon cancer, and development was discontinued in 2013.
Epigenetic regulation of radioresistance: insights from preclinical and clinical studies
Published in Expert Opinion on Investigational Drugs, 2022
Katherine Shishido, Alexis Reinders, Swapna Asuthkar
Perifosine is a synthetic oral alkyl phospholipid [197] that targets the PH domain of AKT1, thereby impairing its localization to the plasma membrane and phosphorylation at S473 and T308 [129] (Figure 4). Clinical trials have indicated that while perifosine is well-tolerated, monotherapy use may not be effective [130,131]. However, it is possible that radiotherapy could enhance the efficacy of perifosine treatment. Vink et al. published a phase I and pharmacokinetic study evaluating the use of perifosine and RT in 21 patients with advanced solid tumors [132]. Patients had either bladder, colon, NSCLC, esophageal, or prostate cancer. Four dose levels of perifosine were assessed, ranging from 50 mg to 200 mg. These dosages were given to patients daily in combination with fractionated radiotherapy. 81% of patients received 3 Gy at 4 fractions per week. At a median follow-up of 10 months, 6 patients showed partial responses and 5 patients showed complete responses. However, after the completion of treatment, over half of the patients developed metastatic progression outside of the irradiated area. This highlights an important consideration that must be made regarding RT and perifosine, as the potential for toxicity might limit its clinical utility.
Performance of capecitabine in novel combination therapies in colorectal cancer
Published in Journal of Chemotherapy, 2021
Fahima Danesh Pouya, Yousef Rasmi, Irem Yalim Camci, Yusuf Tutar, Mohadeseh Nemati
Perifosine is a synthetic alkyl phospholipid with antiproliferative properties in various tumors. Incorporating this compound with tumor cell membranes inhibits the signaling pathways of protein kinase B (AKT), nuclear factor-κB (NF-κB), and the c-Jun N-terminal kinase (JNK) pathways.30,31 Studies on colorectal cell lines have shown that perifosine enhances the effects of fluorouracil by inhibiting the NF-kB pathway. Also, combination therapy of perifosine with CAP in CRC patients reduces drug resistance and improves the effectiveness of CAP.31,32 The results of combining perifosine with radiation therapy have also shown anti-tumor effects;33 therefore, this substance can be used in the treatment of CRC (Figure 1, Table 1).
Targeting AKT for cancer therapy
Published in Expert Opinion on Investigational Drugs, 2019
Maryam Shariati, Funda Meric-Bernstam
Perifosine is a relatively nonselective AKT allosteric inhibitor that disrupts the interaction between AKT and phospholipids in the plasma membrane and triggers apoptosis in vitro and in vivo of human tumor models [96]. Although perifosine displayed significant anti-proliferative activity in preclinical studies, no objective response was observed in a phase II trial of perifosine in pretreated metastatic breast cancer patients [97]. Perifosine plus docetaxel was also assessed in a phase I study in platinum-resistant epithelial ovarian cancer patients [98]. The combination demonstrated evidence of efficacy with acceptable safety profile, but progression-free survival and overall-survival was 1.9 and 4.5 months, respectively. One patient with a PTEN mutation achieved partial remission (PR) for 7.5 months, suggesting that targeting AKT with next generation inhibitors in ovarian cancer having PI3K pathway alterations may be warranted.