Blocking fatty acid synthesis may curb lung cancer growth [PreClinical]

1. ND-646, a small molecule inhibitor of FASyn, an enzyme involved in fatty acid synthesis, caused reduced growth and viability of non-small cell lung cancer (NSCLC) cells in vitro.

2. In two mouse models of NSCLC, ND-646 curbed tumor growth when given as a single agent and in combination with the chemotherapeutic drug carboplatin.

Evidence Rating Level: 2 (Good)

Study Rundown: Because cancer cells are highly proliferative and metabolically active, targeting FASyn in cancer cells has remained a promising approach to hinder overall tumor growth. Despite the importance of FASyn in tumor cells, efforts to develop pharmaceutical approaches to block FASyn have been largely unsuccessful. In this work, the authors described a novel small molecule that inhibited a key FASyn enzyme, acetyl-CoA carboxylase (ACC), and prevented tumor growth in models of NSCLC.

The ACC inhibitor, ND-646, was first tested in vitro in human lung cancer cell lines. As compared to the control treatment, ND-646 led to significantly reduced levels of total fatty acid cell content. Long-term treatment of NSCLC cells resulted in significant loss of cell number, supporting the conclusion that ND-646 induced cancer cell apoptosis. Similar results demonstrating reduced tumor growth and FASyn were obtained when ND-646 was tested in an intravenous (i.v.) xenograft mouse model for NSCLC. In genetic mouse models that spontaneously formed lung tumors, treatment with ND-646 also led to overall reduction of tumor size. This was accompanied by a significant decrease in the number of proliferative tumor cells. When ND-646 was combined with a standard-of-care chemotherapeutic agent, carboplatin, reduction in tumor volume and proliferative cell numbers was most dramatic.

Overall, this work demonstrated the ability for a novel drug, ND-646, to target tumor growth by inihibiting FASyn. Though the results convincingly demonstrated the potential for this drug to slow down the growth of tumors, more work should investigate the ability for ND-646 to extend survival rates while generating few off-target side effects.

Click to read the study in Nature Medicine

Relevant Reading: Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology

In-Depth [animal study]: Efficacy of ND-646 was first tested in vitro in the NSCLC cell line, A549. Treatment for 72 hours with ND-646 led to a nearly 85% decrease in the total amount of fatty acids produced by the cells (p<0.001). Exposure to 500nM ND-646 for 7 days also led to a significant reduction in total cell number as compared to the control-treated group (p<0.001). When the inhibitor-treated group was supplemented with exogenous palmitate (200uM), this decrease was partially rescued, suggesting that the inhibition of FASyn was responsible for the change in cell number.

In the xenograft NSCLC model, A549 cells were delivered by i.v. injection into 8-week-old female SCID mice. Forty-two days after injection, treatment with ND-646 or the vehicle control was initiated for one week. Oral treatment with 50mg/kg ND-646 twice daily led to significant decreases in the levels of palmitate and stearate (p<0.001). Long-term treatment with ND-646 (6 weeks) when initiated 3 weeks after i.v. injection of A549 cells caused an 80% reduction in the tumor area to total lung area ratio (p<0.01).

In the two genetic NSCLC models (Kras;Trp53^-/- and Kras;Stk11^-/-), ND-646 (50mg/kg twice daily) was orally administered with and without intraperitoneal injection of carboplatin (25mg/kg every 3 days). Bioluminescence monitoring of tumors showed reduced average tumor size in mice treated with ND-646 alone versus the vehicle control. Consistently in both genetic models, combination treatment led to greater growth reduction as compared to single agent treatments. Histological evaluation using BrdU staining demonstrated that ND-646 decreased the proportion of proliferative cancer cells in the tumors, with combination therapy again resulting in the most dramatic effect relative to the control group.

Image: PD

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