PF-03084014

PF-03084014 is a reversible and selective inhibitor of γ-secretase with IC50 value of 6.2 nM [1].
The Notch signaling pathway is triggered by the interaction of Notch ligand and Notch receptor located in the membrane of the adjacent cell. Then the NICD fragment is released through the cleavage caused by γ-secretase and subsequently regulates the transcription of the downstream genes. Since Notch signaling pathway appears to be important in the development of many cancers, the small-molecule inhibitors of γ-secretase are now developed as antitumor drugs in cancer treatment. PF-03084014 is one of these GSIs (γ-secretase inhibitors) that showed IC50 value of 6.2 nM in inhibiting the production of Aβ in HeLa cells. Meanwhile PF-03084014 has no significant inhibition effect on other receptors, proteases, ion channels and kinases, demonstrating its selectivity against γ-secretase [1, 2].
In CLL (chronic lymphocytic leukemia) cells from mutated CLL patients, the treatment of 10 μM PF-03084014 induced 29.63% apoptosis. PF-03084014 at concentration of 1 μM induced cell apoptosis with 7.84%. In Notch1-unmutated cells, PF-03084014 induced apoptosis with 22.04% and 4.44% at concentrations of 1 and 10 μM, respectively. PF-03084014 showed no significant apoptosis induction in normal T cells from Notch1-mutated CLL patients. In HPB-ALL cells harboring Notch1 mutations, PF-03084014 inhibited Notch receptor cleavage with IC50 value of 13.3 nM. It also down-regulated the expressions of Hes-1 and cMyc in the cells. It is found that PF-03084014 inhibits cell growth through induce cell cycle arrest at G0-G1 phase [1, 3].
In HPB-ALL tumor xenograft model, oral administration of PF-03084014 at dose of 50 mg/kg inhibited NICD production (70%-80%) after 24 hours. 150 mg/kg PF-03084014 caused maximal tumor growth inhibition of 92%. Besides that, the combination treatment of PF-03084014 and GEM significantly inhibited tumor growth and caused tumor regression in implanted PDA (pancreatic ductal adenocarcinoma) xenografts. It is also reported that the coadministration of PF-03084014 and dexamethasone can abrogate the gastrointestinal toxicity induced by PF-03084014 [1, 4].
References:
1.Wei P, Walls M, Qiu M, et al. Evaluation of selective γ-secretase inhibitor PF-03084014 for its antitumor efficacy and gastrointestinal safety to guide optimal clinical trial design. Molecular cancer therapeutics, 2010, 9(6): 1618-1628.
2.Arcaroli J J, Quackenbush K S, Purkey A, et al. Tumours with elevated levels of the Notch and Wnt pathways exhibit efficacy to PF-03084014, a γ-secretase inhibitor, in a preclinical colorectal explant model. British journal of cancer, 2013, 109(3): 667-675.
3.López-Guerra M, Xargay-Torrent S, Rosich L, et al. The γ-secretase inhibitor PF-03084014 combined with fludarabine antagonizes migration, invasion and angiogenesis in NOTCH1-mutated CLL cells. Leukemia, 2014.
4.Yabuuchi S, Pai S G, Campbell N R, et al. Notch signaling pathway targeted therapy suppresses tumor progression and metastatic spread in pancreatic cancer. Cancer letters, 2013, 335(1): 41-51.

Clinical Activity of the gamma-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors (Aggressive Fibromatosis).[Pubmed:28350521]

J Clin Oncol. 2017 May 10;35(14):1561-1569.

Purpose Desmoid tumors (aggressive fibromatosis) arise from connective tissue cells or fibroblasts. In general, they are slow growing and do not metastasize; however, locally aggressive desmoid tumors can cause severe morbidity and loss of function. Disease recurrence after surgery and/or radiation and diagnosis of multifocal desmoid tumors highlight the need to develop effective systemic treatments for this disease. In this study, we evaluate objective response rate after therapy with the gamma-secretase inhibitor PF-03084014 in patients with recurrent, refractory, progressive desmoid tumors. Patients and Methods Seventeen patients with desmoid tumors received PF-03084014 150 mg orally twice a day in 3-week cycles. Response to treatment was evaluated at cycle 1 and every six cycles, that is, 18 weeks, by RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1. Patient-reported outcomes were measured at baseline and at every restaging visit by using the MD Anderson Symptoms Inventory. Archival tumor and blood samples were genotyped for somatic and germline mutations in APC and CTNNB1. Results Of 17 patients accrued to the study, 15 had mutations in APC or CTNNB1 genes. Sixteen patients (94%) were evaluable for response; five (29%) experienced a confirmed partial response and have been on study for more than 2 years. Another five patients with prolonged stable disease as their best response remain on study. Patient-reported outcomes confirmed clinician reporting that the investigational agent was well tolerated and, in subgroup analyses, participants who demonstrated partial response also experienced clinically meaningful and statistically significant improvements in symptom burden. Conclusion PF-03084014 was well tolerated and demonstrated promising clinical benefit in patients with refractory, progressive desmoid tumors who receive long-term treatment.

Phase I study of the gamma secretase inhibitor PF-03084014 in combination with docetaxel in patients with advanced triple-negative breast cancer.[Pubmed:27906684]

Oncotarget. 2017 Jan 10;8(2):2320-2328.

BACKGROUND: The NOTCH signaling pathway may be involved in the survival of stem cell-like tumor-initiating cells and contribute to tumor growth. In this phase Ib, open-label, multicenter study (NCT01876251), we evaluated PF-03084014, a selective gamma-secretase inhibitor in patients with advanced triple-negative breast cancer. METHODS: The dose-finding part was based on a 2x3 matrix design using the modified toxicity probability interval method. Oral PF-03084014 was administered twice daily continuously in combination with intravenous docetaxel given on day 1 of each 21-day cycle. Primary endpoint was first-cycle dose-limiting toxicity (DLT) for the dose-finding part and 6-month progression-free survival (PFS) for the expansion cohort treated at the maximum tolerated dose (MTD). Secondary endpoints included safety, objective response, and pharmacokinetics of the combination. RESULTS AND CONCLUSIONS: The MTD was estimated to be PF-03084014 100 mg twice daily / docetaxel 75 mg/m2. At this dose level, combination treatment was generally well tolerated (one DLT, grade 3 diarrhea, among eight DLT-evaluable patients). The most common all-grade, treatment-related adverse events reported in all patients (N = 29) were neutropenia (90%), fatigue (79%), nausea (72%), leukopenia (69%), diarrhea (59%), alopecia (55%), anemia (55%), and vomiting (48%). No effect was observed on the pharmacokinetics of docetaxel when administered in combination with PF-03084014. Four (16%) of 25 response-evaluable patients achieved a confirmed partial response; nine (36%) patients had stable disease, including five patients with unconfirmed partial response. In the expansion cohort, median PFS was 4.1 (95% CI 1.3-8.1) months (6-month PFS rate 17.1% [95% CI 0.8-52.6%]).

Notch Pathway Inhibition Using PF-03084014, a gamma-Secretase Inhibitor (GSI), Enhances the Antitumor Effect of Docetaxel in Prostate Cancer.[Pubmed:26202948]

Clin Cancer Res. 2015 Oct 15;21(20):4619-29.

PURPOSE: To investigate the efficacy and mechanisms of Notch signaling inhibition as an adjuvant to docetaxel in castration-resistant prostate cancer (CRPC) using a gamma-secretase inhibitor (GSI), PF-03084014. EXPERIMENTAL DESIGN: The effect of PF-03084014 on response to docetaxel was evaluated in docetaxel-sensitive and docetaxel-resistant CRPC cell lines in vitro and in murine models. Both soft tissue and bone sites were evaluated in vivo. Impacts on cell proliferation, apoptosis, cancer stem cells, and angiogenesis were evaluated. RESULTS: The combination of PF-03084014 plus docetaxel reduced both docetaxel-sensitive and docetaxel-resistant CRPC tumor growth in soft tissue and bone greater than either agent alone. Antitumor activity was associated with PF-03084014-induced inhibition of Notch pathway signaling; decreased survival signals (cyclin E; MEK/ERK, PI3K/AKT, EGFR and NF-kappaB pathway; BCL-2, BCL-XL); increased apoptotic signals (BAK, BAX; cleaved caspase-3); reduced microvessel density; reduced epithelial-mesenchymal transition; and reduced cancer stem-like cells in the tumor. CONCLUSIONS: These results reveal that PF-03084014 enhances docetaxel-mediated tumor response and provides a rationale to explore GSIs as adjunct therapy in conjunction with docetaxel for men with CRPC.