Efficacy of perifosine alone and in combination with sorafenib in an HrasG12V plus shp53 transgenic mouse model of hepatocellular carcinoma

Kim, Seung Up; Ro, Simon Weonsang; Kim, Da Young; Cho, Kyung Ju; Park, Jeon Han; Lim, Ho Yeong; Han, Kwang Hyub

doi:10.1007/s00280-015-2787-7

Cited by 5 publications

(3 citation statements)

References 34 publications

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“…Nevertheless, the PI3K/Akt signaling cascade remains a rational target of interest in MM [29][30][31] and multiple other cancers [32][33][34][35], with several Akt inhibitors in ongoing clinical development either alone or in combination regimens [32,[36][37][38][39], and preclinical data demonstrating the validity of this mechanism of action with perifosine and other agents both in hematological malignancies and solid tumors [40][41][42][43].…”

Section: Discussionmentioning

confidence: 99%

“…Reflecting these findings, a similar lack of OS benefit was seen with the addition of perifosine to capecitabine in patients with metastatic colorectal cancer in the phase 3 X‐PECT study [ 28 ]. Nevertheless, the PI3K/Akt signaling cascade remains a rational target of interest in MM [ 29 , 30 , 31 ] and multiple other cancers [ 32 , 33 , 34 , 35 ], with several Akt inhibitors in ongoing clinical development either alone or in combination regimens [ 32 , 36 , 37 , 38 , 39 ], and preclinical data demonstrating the validity of this mechanism of action with perifosine and other agents both in hematological malignancies and solid tumors [ 40 , 41 , 42 , 43 ]. Meanwhile, additional therapeutic approaches targeted at other signaling cascades of known importance are being explored in RRMM [ 9 , 44 ], warranting further evaluation.…”

Section: Discussionmentioning

confidence: 99%

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Randomized, placebo‐controlled, phase 3 study of perifosine combined with bortezomib and dexamethasone in patients with relapsed, refractory multiple myeloma previously treated with bortezomib

Richardson

Nagler

Ben‐Yehuda

et al. 2020

eJHaem

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Perifosine, an investigational, oral, synthetic alkylphospholipid, inhibits signal transduction pathways of relevance in multiple myeloma (MM) including PI3K/Akt. Perifosine demonstrated anti‐MM activity in preclinical studies and encouraging early‐phase clinical activity in combination with bortezomib. A randomized, double‐blind, placebo‐controlled phase 3 study was conducted to evaluate addition of perifosine to bortezomib‐dexamethasone in MM patients with one to four prior therapies who had relapsed following previous bortezomib‐based therapy. The primary endpoint was progression‐free survival (PFS). The study was discontinued at planned interim analysis, with 135 patients enrolled. Median PFS was 22.7 weeks (95% confidence interval 16·0–45·4) in the perifosine arm and 39.0 weeks (18.3–50.1) in the placebo arm (hazard ratio 1.269 [0.817–1.969]; P = .287); overall response rates were 20% and 27%, respectively. Conversely, median overall survival (OS) was 141.9 weeks and 83.3 weeks (hazard ratio 0.734 [0.380–1.419]; P = .356). Overall, 61% and 55% of patients in the perifosine and placebo arms reported grade 3/4 adverse events, including thrombocytopenia (26% vs 14%), anemia (7% vs 8%), hyponatremia (6% vs 8%), and pneumonia (9% vs 3%). These findings demonstrate no PFS benefit from the addition of perifosine to bortezomib‐dexamethasone in this study of relapsed/refractory MM, but comparable safety and OS.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Randomized, placebo‐controlled, phase 3 study of perifosine combined with bortezomib and dexamethasone in patients with relapsed, refractory multiple myeloma previously treated with bortezomib

Richardson

Nagler

Ben‐Yehuda

et al. 2020

eJHaem

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“…Plasmids. The plasmids, pT2/EGFP, pT2/HRAS G12V , pT2/shp53, pT2/c-Myc, and pPGK-SB13 have been previously described (22,23). The plasmid, pT2/c-Myc T58A was constructed via site-directed mutagenesis replacing ACC (encoding threonine) at codon 58 of the c-Myc with GCC (encoding alanine).…”

Section: Methodsmentioning

confidence: 99%

c-Myc-driven Hepatocarcinogenesis

Moon

Park

2021

Anticancer Res

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Background/Aim: Dysregulation of the c-Myc gene is frequently found in human hepatocellular carcinoma (HCC), often accompanied by genetic and epigenetic alterations in other cancer-related genes. Here, we investigated the tumorigenic potential of c-Myc in diverse genetic environments in which the Ras, Wnt/β-catenin, Sonic hedgehog, or P53 pathways were either activated or inactivated. Materials and Methods: Hydrodynamic tail vein injection was employed to administer expression transposons and generate transgenic livers expressing c-Myc together with a constitutively active form of RAS (HRAS G12V ), βcatenin (β-catenin S33Y ), Smo (SmoM2), or short hairpin RNA targeting P53 (shp53). Results: c-Myc was most tumorigenic when the RAS signaling pathway was activated, whereas no tumors were found in mice when either β-catenin S33Y or SmoM2 was co-expressed with c-Myc. Approximately 40% of mice had HCC when c-Myc was over-expressed under P53 inactivation. Furthermore, we investigated the effect of mutation in c-Myc on hepatocarcinogenesis. Conclusion: No significant differences in tumorigenic potential were found between wild type c-Myc and c-Myc T58A , minimizing the role of the mutation in hepatocarcinogenesis.

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Preclinical efficacy of a novel dual PI3K/mTOR inhibitor, CMG002, alone and in combination with sorafenib in hepatocellular carcinoma

Kim

Lee

Kim³

et al. 2019

Cancer Chemother Pharmacol

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Efficacy of perifosine alone and in combination with sorafenib in an HrasG12V plus shp53 transgenic mouse model of hepatocellular carcinoma

Abstract: The preclinical effect that current study showed represents a strong rationale for clinical trials using perifosine alone and in combination with sorafenib in the treatment of HCC patients.

Cited by 5 publications

References 34 publications

Randomized, placebo‐controlled, phase 3 study of perifosine combined with bortezomib and dexamethasone in patients with relapsed, refractory multiple myeloma previously treated with bortezomib

Randomized, placebo‐controlled, phase 3 study of perifosine combined with bortezomib and dexamethasone in patients with relapsed, refractory multiple myeloma previously treated with bortezomib

c-Myc-driven Hepatocarcinogenesis

Preclinical efficacy of a novel dual PI3K/mTOR inhibitor, CMG002, alone and in combination with sorafenib in hepatocellular carcinoma

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