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Targeting PIM kinase enhances the activity of sunitinib in renal cell carcinoma

D Mahalingam1, C M Espitia, E C Medina

  • 1Department of Medicine, Institute for Drug Development, Cancer Therapy and Research Center, The University of Texas Health Science Center, 7979 Wurzbach Road, San Antonio, TX 78245, USA.

British Journal of Cancer
|October 22, 2011
PubMed
Abstract

Insights

Targeting PIM kinase with SGI-1776 shows promise for renal cell carcinoma (RCC) treatment. Combining SGI-1776 with sunitinib enhances anticancer activity and reduces tumor burden in RCC models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • PIM kinase upregulation is observed in various cancers, indicating its potential as a therapeutic target.
  • Renal cell carcinoma (RCC) is a malignancy where PIM kinase activity may be inhibited for treatment.
  • SGI-1776 is a novel small molecule inhibitor targeting PIM kinase activity.

Purpose of the Study:

  • To investigate the effect of SGI-1776 on renal cell carcinoma (RCC) cell viability.
  • To evaluate the synergistic effect of SGI-1776 combined with sunitinib in RCC.
  • To determine the role of c-Myc in the response to PIM kinase inhibition and sunitinib.

Main Methods:

  • Utilized immunoblotting, qRT-PCR, and gene expression arrays to identify genes affected by SGI-1776.
  • Assessed anticancer activity through in vitro viability and apoptosis assays.
  • Evaluated efficacy in vivo using RCC tumor xenograft models.

Main Results:

  • SGI-1776 treatment decreased phosphorylated and total c-Myc levels, modulating c-Myc target genes.
  • The combination of SGI-1776 and sunitinib further reduced c-Myc and enhanced anticancer activity.
  • Combination therapy significantly reduced tumor burden in RCC xenografts with good tolerability.

Conclusions:

  • Targeting PIM kinase signaling represents a promising therapeutic strategy for renal cell carcinoma (RCC).
  • The combination of SGI-1776 and sunitinib demonstrates significant efficacy in preclinical RCC models.
  • c-Myc plays a crucial role in mediating sensitivity to this combination therapy.

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