Editors' ChoiceCancer

Triple threat to colorectal cancer

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Science Translational Medicine  17 Aug 2016:
Vol. 8, Issue 352, pp. 352ec132
DOI: 10.1126/scitranslmed.aai7458

Colorectal cancer is the third most common cause of cancer death in the United States and the second in Europe. Surgical tumor resection combined with chemotherapy often leads to disease remission but is associated with many complications and relapse occurs in 30 to 50% of patients. Available therapies for prevention of recurrence and metastasis in colorectal cancer demonstrate both limited efficacy and capacity to differentiate between cancerous and healthy cells and tissues. Therefore, new, more effective therapeutic approaches for colorectal cancer with fewer toxic side effects are greatly needed.

To address this, Conde et al. utilized localized gene and drug delivery with phototherapy, or light-based therapy, for tumor ablation to improve therapeutic efficacy over systemic or intratumoral administration in a preclinical mouse model of colorectal cancer, both in terms of tumor shrinkage and survival rate. The authors embedded biomaterial hydrogels with a variety of gold nanoparticle conjugates. Short interfering RNA conjugates enabled knockdown of genes important to cancer progression, and drug conjugates mediated inhibition of cancer cell proliferation. Irradiating the nanoparticles with near-infrared radiation delivered local phototherapy to the tumor. As a prophylactic hydrogel patch, this combination therapy approach prevented tumor recurrence after resection and eliminated the need for tumor resection when administered as a neoadjuvant therapy. By studying the host response to local administration of the therapeutic hydrogel doped with nanoparticles by molecular and gene pathway analysis, they found phototherapy treatment led to induction of molecular pathways regulated by genes controlling intracellular transport, whereas both gene therapy and chemotherapy stimulated transcription and metabolism mechanisms. Triple therapy increased the number of pathways altered over time post treatment, including genes associated with apoptosis and survival, stress response, chemotaxis, and regulation of the extracellular matrix.

This study suggests that therapies localized to the tumor microenvironment might be more effective in combating colon cancers than systemically administered treatments that have high potential for off-target effects. These results also demonstrate that the combination of multiple therapeutic interventions inducing different host responses can synergize to achieve improved therapeutic effects. The authors also suggest that colonoscopy equipment could be used in future work to deliver triple therapy hydrogels in a minimally invasive manner directly to colonic tumors to potentially improve therapeutic outcomes.

J. Conde et al., Local triple-combination therapy results in tumour regression and prevents recurrence in a colon cancer model. Nat. Mater. 10.1038/nmat4707 (2016). [Abstract]

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