The anti-myeloma effects of the selective JAK1 inhibitor (INCB052793) alone and in combination in vitro and in vivo

Sanchez, Eric; Li, Mingjie; Patil, Saurabh; Soof, Camilia; Nosrati, Jason D.; Schlossberg, Remy; Vidisheva, Aleksandra; Tanenbaum, Edward J; Hekmati, Tara; Zahab, Brian; Wang, Cathy; Tang, George; Chen, Haiming; Berenson, James R.

doi:10.1007/s00277-019-03595-0

Cited by 16 publications

(27 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, these studies provide the rationale for treating MM patients with JAK inhibitors to both target tumour stimulatory M2 cells and block resistance of tumour cells to active immunomodulatory agents, such as LEN. In support of this, a phase 1 clinical trial has recently shown that the addition of RUX to LEN and steroids can frequently reverse resistance of MM patients to the latter two drugs (Berenson et al , ), which is also consistent with our preclinical in vivo studies (Sanchez et al , ). A recent study found that PD‐L1 (also termed CD274) and another immune checkpoint molecule IDO (also termed IDO1) were upregulated in tumour‐associated TAMs (M2) after treatment with trastuzumab in HER2+ breast cancer patients.…”

Section: Discussionsupporting

confidence: 79%

“…In support of the potential role of JAK inhibitors for the treatment of MM based on these findings, we have shown that ruxolitinib (RUX) overcomes resistance of MM patients to lenalidomide (LEN) in an ongoing clinical trial (Berenson et al , ). In addition, we have also recently shown that the JAK inhibitor INCB052793 demonstrates anti‐MM effects both in vitro and in vivo and increases the anti‐MM effects of LEN (Sanchez et al , ). In the current study, we investigated the relationship of the clinical status of MM patients to macrophage polarization and the impact of the JAK inhibitor RUX on M1/M2 macrophage status.…”

mentioning

confidence: 88%

See 1 more Smart Citation

JAK1/2 pathway inhibition suppresses M2 polarization and overcomes resistance of myeloma to lenalidomide by reducing TRIB1, MUC1, CD44, CXCL12, and CXCR4 expression

Chen

Sanchez

et al. 2019

Br J Haematol

Self Cite

View full text Add to dashboard Cite

Monocytes polarize into pro-inflammatory macrophage-1 (M1) or alternative macrophage-2 (M2) states with distinct phenotypes and physiological functions. M2 cells promote tumour growth and metastasis whereas M1 macrophages show anti-tumour effects. We found that M2 cells were increased whereas M1 cells were decreased in bone marrow (BM) from multiple myeloma (MM) patients with progressive disease (PD) compared to those in complete remission (CR). Gene expression of Tribbles homolog 1 (TRIB1) protein kinase, an inducer of M2 polarization, was increased in BM from MM patients with PD compared to those in CR. Ruxolitinib (RUX) is an inhibitor of the Janus kinase family of protein tyrosine kinases (JAKs) and is effective for treating patients with myeloproliferative disorders. RUX markedly reduces both M2 polarization and TRIB1 gene expression in MM both in vitro and in vivo in human MM xenografts in severe combined immunodeficient mice. RUX also downregulates the expression of CXCL12, CXCR4, MUC1, and CD44 in MM cells and monocytes co-cultured with MM tumour cells; overexpression of these genes is associated with resistance of MM cells to the immunomodulatory agent lenalidomide. These results provide the rationale for evaluation of JAK inhibitors, including MM BM in combination with lenalidomide, for the treatment of MM patients.

show abstract

Section: Discussionsupporting

confidence: 79%

mentioning

confidence: 88%

JAK1/2 pathway inhibition suppresses M2 polarization and overcomes resistance of myeloma to lenalidomide by reducing TRIB1, MUC1, CD44, CXCL12, and CXCR4 expression

Chen

Sanchez

et al. 2019

Br J Haematol

Self Cite

View full text Add to dashboard Cite

show abstract

“…INCB052793 has been studied in multiple myeloma (MM) preclinical models, but there are no reports using this agent in solid tumors. In combination with other anti-MM agents, INCB052793 decreased cell viability and inhibited tumor growth [112] . A Phase I/II trial was initiated investigating this agent in solid tumors but was terminated due to lack of efficacy (NCT02265510).…”

Section: Incb047986 and Incb052793mentioning

confidence: 99%

Targeting the JAK/STAT pathway in solid tumors

Qureshy¹,

Johnson²,

Grandis³

2020

JCMT

View full text Add to dashboard Cite

Aberrant activation of signal transducer and activator of transcription (STAT) proteins is associated with the development and progression of solid tumors. However, as transcription factors, these proteins are difficult to target directly. In this review, we summarize the role of targeting Janus kinases (JAKs), upstream activators of STATs, as a strategy for decreasing STAT activation in solid tumors. Preclinical studies in solid tumor cell line models show that JAK inhibitors decrease STAT activation, cell proliferation, and cell survival; in in vivo models, they also inhibit tumor growth. JAK inhibitors, particularly the JAK1/2 inhibitor ruxolitinib, sensitize cell lines and murine models to chemotherapy, immunotherapy, and oncolytic viral therapy. Ten JAK inhibitors have been or are actively being tested in clinical trials as monotherapy or in combination with other agents in patients with solid tumors; two of these inhibitors are already Food and Drug Administration (FDA) approved for the treatment of myeloproliferative disorders and rheumatoid arthritis, making them attractive agents for use in patients with solid tumors as they are known to be well-tolerated. Four JAK inhibitors (two of which are FDA approved for other indications) have exhibited promising anti-cancer effects in preclinical studies; however, clinical studies specifically assessing their activity against the JAK/STAT pathway in solid tumors have not yet been conducted. In summary, JAK inhibition is a viable option for targeting the JAK/STAT pathway in solid tumors and merits further testing in clinical trials.

show abstract

“…The pan-JAK2 inhibitor ruxolitinib, by reducing levels of phosphorylation of STAT-Ser-727 in neutrophils that have only a few mitochondria, can globally reduce autophagy induction and potentially revert the pro-inflammatory contribution of neutrophils to MM survival. An encouraging report to this end has been recently published [50], disclosing that the selective JAK1 inhibitor INCB052793 can inhibit cell viability of MM cells when used alone or in combination with proteasome inhibitors and glucocorticosteroids. Further studies are required to address the clinical benefit of JAK/STAT inhibitors in reducing the intracellular effects of pro-inflammatory cytokines released by MM cells in the microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Plasticity of High-Density Neutrophils in Multiple Myeloma is Associated with Increased Autophagy Via STAT3

Puglisi

Parrinello

Giallongo

et al. 2019

IJMS

View full text Add to dashboard Cite

In both monoclonal gammopathy of uncertain significance (MGUS) and multiple myeloma (MM) patients, immune functions are variably impaired, and there is a high risk of bacterial infections. Neutrophils are the most abundant circulating leukocytes and constitute the first line of host defense. Since little is known about the contribution of autophagy in the neutrophil function of MGUS and MM patients, we investigated the basal autophagy flux in freshly sorted neutrophils of patients and tested the plastic response of healthy neutrophils to soluble factors of MM. In freshly sorted high-density neutrophils obtained from patients with MGUS and MM or healthy subjects, we found a progressive autophagy trigger associated with soluble factors circulating in both peripheral blood and bone marrow, associated with increased IFNγ and pSTAT3S727. In normal high-density neutrophils, the formation of acidic vesicular organelles, a morphological characteristic of autophagy, could be induced after exposure for three hours with myeloma conditioned media or MM sera, an effect associated with increased phosphorylation of STAT3-pS727 and reverted by treatment with pan-JAK2 inhibitor ruxolitinib. Taken together, our data suggest that soluble factors in MM can trigger contemporary JAK2 signaling and autophagy in neutrophils, targetable with ruxolitinib.

show abstract

The anti-myeloma effects of the selective JAK1 inhibitor (INCB052793) alone and in combination in vitro and in vivo

Cited by 16 publications

References 29 publications

JAK1/2 pathway inhibition suppresses M2 polarization and overcomes resistance of myeloma to lenalidomide by reducing TRIB1, MUC1, CD44, CXCL12, and CXCR4 expression

JAK1/2 pathway inhibition suppresses M2 polarization and overcomes resistance of myeloma to lenalidomide by reducing TRIB1, MUC1, CD44, CXCL12, and CXCR4 expression

Targeting the JAK/STAT pathway in solid tumors

Plasticity of High-Density Neutrophils in Multiple Myeloma is Associated with Increased Autophagy Via STAT3

Contact Info

Product

Resources

About