Abstract P6-21-07: The stapled peptide ALRN-6924, a dual inhibitor of MDMX and MDM2, and the CDK4/6 inhibitors palbociclib or abemaciclib synergistically enhance each other'sin vitroandin vivoanticancer activity

Author(s):  
A Annis ◽  
LA Carvajal ◽  
J-G Ren ◽  
D Sutton ◽  
S Santiago ◽  
...  
Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4066-4066 ◽  
Author(s):  
David A Sallman ◽  
Uma Borate ◽  
Elizabeth H. Cull ◽  
William B. Donnellan ◽  
Rami S. Komrokji ◽  
...  

Abstract Background: ALRN-6924, the first-ever clinical stage stapled peptide, has been structurally stabilized ("stapled") in an α-helical configuration, to mimic the inhibitor-binding region of the intracellular tumor suppressor protein, p53. By mimicking this region, ALRN-6924 binds the two most important endogenous inhibitors of p53, murine double minute-X (MDMX) and murine double minute-2 (MDM2), thereby restoring p53's ability to induce cell cycle arrest and apoptosis in TP53 wild-type (WT) cancer cells. ALRN-6924 is the first known synthetic agent to simultaneously target both of these important p53 inhibitors. In preclinical studies, ALRN-6924 inhibited the proliferation of AML cell lines and primary human AML cells alone and in combination with cytarabine. Preclinical data (Carvajal et al, 2018) demonstrated antiproliferative effects against leukemic stem cells, and complete responses that translated into cures in approximately 40% of mice in xenotransplantation studies. These data also suggested that more frequent dosing may enhance efficacy, and this hypothesis is now being evaluated in the ongoing clinical trial. Methods: ALRN-6924 is being evaluated alone and in combination with cytarabine, using a 3+3 dose escalation design. Using the previously determined RP2D for solid tumors (Meric-Bernstam et al., 2017), the initial cohorts receive 3.1 mg/kg of ALRN-6924 IV over 1 hour on Days 1, 8, and 15 of a 28-day cycle (QW mono-therapy). In separate cohorts, ALRN-6924 is combined with cytarabine IV over 1 hour (initially 100 mg/m2, later 200 mg/m2 ; QW combo-therapy). Later monotherapy cohorts receive more frequent ALRN-6924 administration on Days 1, 3, 5, 8, 10, and 12 of a 21-day cycle (TIW mono-therapy), with an initial dose level of 2.7 mg/kg. Adverse events (AEs) are assessed per CTCAE V4.03; responses are evaluated by the investigators according to IWG (Cheson 2006) and AML Response Criteria (Dohner 2010), for MDS and AML, respectively. Results: Preliminary results are being presented for 13 pts on QW mono- and 19 pts on QW combo-therapy. As of 13 July 2018, 32 QW pts have enrolled, with a median age of 75 years (38-90), 18 pts with de novo or secondary AML and 14 pts with MDS who failed hypomethylating agents. Thus far, pts have received 1-14 cycles. No DLTs have been observed and no MTD has been reached for QW mono-therapy (3.1-5.8 mg/kg) or QW combo-therapy (3.1-4.4 mg/kg ALRN-6924 and 100-200 mg/m2 cytarabine). For QW-treated pts (mono and combo), AEs related to treatment with ALRN-6924 have been reported in 62.5% of pts; most frequent are nausea (25.0%), thrombocytopenia (25.0%), vomiting (25.0%), fatigue (15.6%), and diarrhea (15.6%). Hyperbilirubinemia was reported in 18.8% of pts, representing a known transient effect of ALRN-6924 clearance that has not been associated with liver injury. Thrombocytopenia is the only ≥ grade 3 hematologic AE related to treatment with ALRN-6924 that was reported in ≥5% of pts, with all cases being grade 4 thrombocytopenia (7 pts, 21.9%). SAEs related to treatment with ALRN-6924 have been reported in 2 pts (grade 3 extremity pain and grade 4 angioedema while on concomitant lisinopril). The AE profiles for pts receiving ALRN-6924 QW mono- or QW combo-therapy were not significantly different. Including all QW cohorts (mono and combo), twenty-seven pts are efficacy-evaluable as of July 13, 2018. In preliminary efficacy results across all cohorts, marrow CR was reported in two out of four MDS pts treated with 4.4 mg/kg ALRN-6924 + 200 mg/m2 cytarabine, one of whom went on to transplant. An additional three MDS pts achieved SD. Among AML pts, 1 had a >50% reduction in bone marrow blasts while receiving 3.1 and then 4.4 mg/kg ALRN-6924 plus 100 mg/m2 cytarabine QW. This was durable until the pt succumbed to pneumonia that was unrelated to study drug in cycle 7. For QW-treated pts (mono and combo), main reasons for treatment discontinuation include treatment failure (31.2%), consent withdrawn (25.0%), death (9.4%), MDS transformed to AML (6.2%), and adverse event (6.2%). Accrual to QW combo-therapy with cytarabine in MDS and TIW mono-therapy in AML and MDS continues; updated data for QW mono-, QW-combo as well as TIW mono-therapy will be presented at the meeting. Conclusion: ALRN-6924 has shown clinical activity and an acceptable safety profile in AML and MDS. Continued development of ALRN-6924 for AML and MDS treatment is warranted. Disclosures Sallman: Celgene: Research Funding, Speakers Bureau. Borate:Agios: Consultancy; Novartis: Consultancy. Cull:Celgene: Speakers Bureau. Komrokji:Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Steidl:Aileron: Consultancy, Research Funding. Corvez:Aileron Therapeutics Inc.: Employment, Equity Ownership. Payton:Aileron Therapeutics: Employment, Equity Ownership. Annis:Aileron Therapeutics Inc.: Employment, Equity Ownership, Patents & Royalties. Pinchasik:Aileron Therapeutics Inc.: Employment, Equity Ownership. Aivado:Aileron Therapeutics Inc.: Employment, Equity Ownership, Patents & Royalties.


2018 ◽  
Author(s):  
Sarah E. Woodfield ◽  
Roma H. Patel ◽  
Aryana M. Ibarra ◽  
Zhenghu Chen ◽  
Sanjeev A. Vasudevan

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sarah E. Woodfield ◽  
Yan Shi ◽  
Roma H. Patel ◽  
Zhenghu Chen ◽  
Aayushi P. Shah ◽  
...  

AbstractHepatoblastoma (HB) is the most common pediatric liver malignancy. High-risk patients have poor survival, and current chemotherapies are associated with significant toxicities. Targeted therapies are needed to improve outcomes and patient quality of life. Most HB cases are TP53 wild-type; therefore, we hypothesized that targeting the p53 regulator Murine double minute 4 (MDM4) to reactivate p53 signaling may show efficacy. MDM4 expression was elevated in HB patient samples, and increased expression was strongly correlated with decreased expression of p53 target genes. Treatment with NSC207895 (XI-006), which inhibits MDM4 expression, or ATSP-7041, a stapled peptide dual inhibitor of MDM2 and MDM4, showed significant cytotoxic and antiproliferative effects in HB cells. Similar phenotypes were seen with short hairpin RNA (shRNA)-mediated inhibition of MDM4. Both NSC207895 and ATSP-7041 caused significant upregulation of p53 targets in HB cells. Knocking-down TP53 with shRNA or overexpressing MDM4 led to resistance to NSC207895-mediated cytotoxicity, suggesting that this phenotype is dependent on the MDM4-p53 axis. MDM4 inhibition also showed efficacy in a murine model of HB with significantly decreased tumor weight and increased apoptosis observed in the treatment group. This study demonstrates that inhibition of MDM4 is efficacious in HB by upregulating p53 tumor suppressor signaling.


2019 ◽  
Vol 2019 ◽  
Author(s):  
Wei Jiang ◽  
Liang Jin ◽  
Min Liu ◽  
Peng Hou ◽  
Wang-Xiao He

2020 ◽  
Vol 20 ◽  
Author(s):  
En Xu ◽  
Hao Zhu ◽  
Feng Wang ◽  
Ji Miao ◽  
Shangce Du ◽  
...  

: Gastric cancer is one of the most common malignancies worldwide and the third leading cause of cancer-related death. In the present study, we investigated the potential activity of OSI-027, a potent and selective mammalian target of rapamycin complex 1/2 (mTOR1/2) dual inhibitor, alone or in combination with oxaliplatin against gastric cancer cells in vitro. Cell counting kit-8 assays and EdU staining were performed to examine the proliferation of cancer cells. Cell cycle and apoptosis were detected by flow cytometry. Western blot was used to detect the elements of the mTOR pathway and Pgp in gastric cancer cell lines. OSI-027 inhibited the proliferation of MKN-45 and AGS cells by arresting the cell cycle in the G0/G1 phase. At the molecular level, OSI-027 simultaneously blocked mTORC1 and mTORC2 activation, and resulted in the downregulation of phosphor-Akt, phpspho-p70S6k, phosphor-4EBP1, cyclin D1, and cyclin-dependent kinase4 (CDK4). Additionally, OSI-027 also downregulated P-gp, which enhanced oxaliplatin-induced apoptosis and suppressed multidrug resistance. Moreover, OSI-027 exhibited synergistic cytotoxic effects with oxaliplatin in vitro, while a P-gp siRNA knockdown significantly inhibited the synergistic effect. In summary, our results suggest that dual mTORC1/mTORC2 inhibitors (e.g., OSI-027) should be further investigated as a potential valuable treatment for gastric cancer.


Sign in / Sign up

Export Citation Format

Share Document