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PI3K/p110{delta} is a novel therapeutic target in multiple myeloma
Hiroshi Ikeda1, Teru Hideshima, Mariateresa Fulciniti
1Lebow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Harvard Medical School, Boston, MA, USA.
Abstract:
In this study, we demonstrate expression and examined the biologic sequelae of PI3K/p110delta signaling in multiple myeloma (MM). Knockdown of p110delta by small interfering RNA caused significant inhibition of MM cell growth. Similarly, p110delta specific small molecule inhibitor CAL-101 triggered cytotoxicity against LB and INA-6 MM cell lines and patient MM cells, associated with inhibition of Akt phosphorylation. In contrast, CAL-101 did not inhibit survival of normal peripheral blood mononuclear cells. CAL-101 overcame MM cell growth conferred by interleukin-6, insulin-like growth factor-1, and bone marrow stromal cell coculture. Interestingly, inhibition of p110delta potently induced autophagy. The in vivo inhibition of p110delta with IC488743 was evaluated in 2 murine xenograft models of human MM: SCID mice bearing human MM cells subcutaneously and the SCID-hu model, in which human MM cells are injected within a human bone chip implanted subcutaneously in SCID mice. IC488743 significantly inhibited tumor growth and prolonged host survival in both models. Finally, combined CAL-101 with bortezomib induced synergistic cytotoxicity against MM cells. Our studies therefore show that PI3K/p110delta is a novel therapeutic target in MM and provide the basis for clinical evaluation of CAL-101 to improve patient outcome in MM.
Insights
Targeting PI3K/p110delta with CAL-101 shows promise for multiple myeloma (MM). This inhibitor reduced MM cell growth and overcame resistance, offering a new therapeutic strategy for MM patients.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Multiple myeloma (MM) is a hematologic malignancy with limited therapeutic options.
- Phosphoinositide 3-kinase (PI3K) signaling pathways are implicated in cancer cell proliferation and survival.
- The p110delta isoform of PI3K is a potential therapeutic target in various cancers.
Purpose of the Study:
- To investigate the role of PI3K/p110delta signaling in multiple myeloma.
- To evaluate the efficacy of p110delta inhibition as a therapeutic strategy for MM.
- To assess the safety and synergistic potential of p110delta inhibitors in MM.
Main Methods:
- Small interfering RNA (siRNA) was used to knockdown p110delta expression in MM cells.
- The p110delta-specific inhibitor CAL-101 was tested for cytotoxicity against MM cell lines and patient cells.
- In vivo efficacy was assessed using murine xenograft models of human MM.
- Synergistic effects were evaluated by combining CAL-101 with bortezomib.
Main Results:
- p110delta knockdown and CAL-101 treatment significantly inhibited MM cell growth and induced cytotoxicity.
- CAL-101 demonstrated selectivity, sparing normal peripheral blood mononuclear cells.
- CAL-101 overcame MM cell growth resistance induced by cytokines and stromal cells.
- Inhibition of p110delta induced autophagy and significantly reduced tumor growth in vivo.
- Combined CAL-101 and bortezomib exhibited synergistic cytotoxicity against MM cells.
Conclusions:
- PI3K/p110delta is a novel and effective therapeutic target in multiple myeloma.
- CAL-101 demonstrates potent anti-myeloma activity both in vitro and in vivo.
- CAL-101 warrants further clinical investigation for the treatment of MM patients.
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