Protein Translation Inhibition is Involved in the Activity of the Pan-PIM Kinase Inhibitor PIM447 in Combination with Pomalidomide-Dexamethasone in Multiple Myeloma

Paíno, Teresa; González-Méndez, Lorena; San-Segundo, Laura; Corchete, Luis A.; Hernández-García, Susana; Díaz-Tejedor, Andrea; Algarín, Esperanza M.; Mogollón, Pedro; Martín-Sánchez, Montserrat; Gutiérrez, Norma C.; Mateos, María Victoria; Garayoa, Mercedes; Ocio, Enrique M.

doi:10.3390/cancers12102743

Cited by 10 publications

(14 citation statements)

References 54 publications

(82 reference statements)

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“…Results of new pharmacological combinations of PIM447 with other anti-myeloma agents have demonstrated a synergistic effect in MM in a preclinical study [ 78 ]. This study showed that PIM447 in combination with the standard treatment pomalidomide + dexamethasone exerts a potent antitumor effect and significantly improves survival with respect to the standard treatment.…”

Section: Pim Kinase Inhibitorsmentioning

confidence: 99%

PIM Kinases in Multiple Myeloma

Chu

Kang

2021

Cancers

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Multiple myeloma (MM) remains an incurable disease and novel therapeutic agents/approaches are urgently needed. The PIM (Proviral insertion in murine malignancies) serine/threonine kinases have 3 isoforms: PIM1, PIM2, and PIM3. PIM kinases are engaged with an expansive scope of biological activities including cell growth, apoptosis, drug resistance, and immune response. An assortment of molecules and pathways that are critical to myeloma tumorigenesis has been recognized as the downstream targets of PIM kinases. The inhibition of PIM kinases has become an emerging scientific interest for the treatment of multiple myeloma and several PIM kinase inhibitors, such as SGI-1776, AZD1208, and PIM447 (formerly LGH447), have been developed and are under different phases of clinical trials. Current research has been focused on the development of a new generation of potent PIM kinase inhibitors with appropriate pharmacological profiles reasonable for human malignancy treatment. Combination therapy of PIM kinase inhibitors with chemotherapeutic appears to create an additive cytotoxic impact in cancer cells. Notwithstanding, the mechanisms by which PIM kinases modulate the immune microenvironment and synergize with the immunomodulatory agents such as lenalidomide have not been deliberately depicted. This review provides a comprehensive overview of the PIM kinase pathways and the current research status of the development of PIM kinase inhibitors for the treatment of MM. Additionally, the combinatorial effects of the PIM kinase inhibitors with other targeted agents and the promising strategies to exploit PIM as a therapeutic target in malignancy are highlighted.

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Section: Pim Kinase Inhibitorsmentioning

confidence: 99%

PIM Kinases in Multiple Myeloma

Chu

Kang

2021

Cancers

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“…Taken together, while PIM-inhibition showed promising activity in a phase I study, there are currently no clinical trials examining this further. While there is preclinical rationale for combining PIM-inhibition with pomalidomide and dexamethasone [ 107 ], which leads to downregulation of IRF4 and convergently inhibits protein translation through inhibition of mTORC1 and c-MYC, there are so far no studies examining combination therapies as further development of this compound has been abandoned.…”

Section: Pim-directed Therapiesmentioning

confidence: 99%

Pathway-Directed Therapy in Multiple Myeloma

John

Krauth

Podar

et al. 2021

Cancers

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Multiple Myeloma (MM) is a malignant plasma cell disorder with an unmet medical need, in particular for relapsed and refractory patients. Molecules within deregulated signaling pathways, including the RAS/RAF/MEK/ERK, but also the PI3K/AKT-pathway belong to the most promising evolving therapeutic targets. Rationally derived compounds hold great therapeutic promise to target tumor-specific abnormalities rather than general MM-associated vulnerabilities. This paradigm is probably best depicted by targeting mutated BRAF: while well-tolerated, remarkable responses have been achieved in selected patients by inhibition of BRAFV600E alone or in combination with MEK. Targeting of AKT has also shown promising results in a subset of patients as monotherapy or to resensitize MM-cells to conventional treatment. Approaches to target transcription factors, convergence points of signaling cascades such as p53 or c-MYC, are emerging as yet another exciting strategy for pathway-directed therapy. Informed by our increasing knowledge on the impact of signaling pathways in MM pathophysiology, rationally derived Precision-Medicine trials are ongoing. Their results are likely to once more fundamentally change treatment strategies in MM.

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“…In line with what others proposed for different small-molecule inhibitors, the authors demonstrated a strong synergistic effect with standard of care agents (IMiDs and PIs), supporting the use of this combination to treat MM patients [ 86 ] . In fact, in a more recent publication, the same authors used one of these combinations (PIM447 plus pomalidomide and dexamethasone) and showed improved survival in a preclinical mouse model, where they revealed a convergent blockage of MYC and mTORC1, disrupting the function of eIF4e (Eukaryotic translation Initiation Factor 4E), an essential element of the Initiation Translation Complex [ 128 ] , and downregulating IRF4, important in many immune-related contexts [ 129 ] , as happened with several BETi [ 87 ] . Interestingly, Buettner et al [ 89 ] presented a similar effect by leflunomide, an orally available, non-toxic, inexpensive immunosuppressive drug regularly used to treat rheumatoid arthritis.…”

Section: Myc Inhibition Strategiesmentioning

confidence: 99%