Improved antitumor activity against prostate cancer via synergistic targeting of Myc and GFAT-1

Inhibition of Myc promotes the regression of many types of tumors, including prostate cancer. However, the success of anti-Myc therapy is hampered by the lack of a strategy to effectively deliver the inhibitors to the tumor site and by the feedback mechanisms that cancer cells use to adapt to metabolic reprogramming. 

Methods: The effects of Myc inhibitors (10074-G5 or 10058-F4), alone or in combination with 6-diazo-5-oxo-L-norleucine (DON), were evaluated in cultured human or murine prostate cancer cells by cell viability assay, qRT-PCR and Western blot. To facilitate the in vivo therapeutic evaluation, a prodrug conjugate of 10074-G4 and DON (10074-DON) was developed, which could be effectively loaded into a polysaccharide-based nanocarrier (PS). 

Results: The treatment with Myc inhibitors led to significant induction of glutamine: fructose-6-phosphate amidotransferase-1 (GFAT1) and enhanced protein glycosylation. Mechanistically, Myc inhibition triggered GFAT1 induction through the IREα-Xbp1s pathway. The combination use of Myc inhibitors and GFAT1 inhibitor DON led to a synergistic effect in inhibiting the proliferation and migration of prostate cancer cells. Enhanced in vivo delivery of 10074-DON via the PS nanocarrier led to a significant inhibition of tumor growth along with an improvement in tumor immune microenvironment in several PCa animal models. 

Conclusion: Simultaneous targeting of Myc and GFAT-1 may represent a novel strategy for the treatment of prostate cancer.

 

Comments:

The passage you provided describes a study that investigated the effects of inhibiting Myc, a protein associated with tumor growth, on prostate cancer. The researchers aimed to overcome the challenges of delivering Myc inhibitors to the tumor site and the feedback mechanisms that cancer cells use to adapt to metabolic changes.

The study evaluated the effects of two Myc inhibitors, 10074-G5 and 10058-F4, alone or in combination with a GFAT1 inhibitor called 6-diazo-5-oxo-L-norleucine (DON), in cultured human or murine prostate cancer cells. The researchers assessed cell viability, gene expression using quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and protein levels using Western blot analysis.

The results showed that treatment with Myc inhibitors led to the induction of GFAT1, an enzyme involved in protein glycosylation, and increased protein glycosylation. This induction occurred through the IREα-Xbp1s pathway, which is a signaling pathway involved in cellular stress response. When the Myc inhibitors were combined with the GFAT1 inhibitor DON, they synergistically inhibited the proliferation and migration of prostate cancer cells.

To enhance the delivery of Myc inhibitor DON in vivo, the researchers developed a prodrug conjugate called 10074-DON, which could be loaded into a polysaccharide-based nanocarrier (PS). Using this approach, they observed significant inhibition of tumor growth and improvement in the tumor immune microenvironment in various animal models of prostate cancer.

In conclusion, the study suggests that targeting both Myc and GFAT1 simultaneously may be a promising strategy for the treatment of prostate cancer. The researchers demonstrated that inhibiting Myc and GFAT1 in combination had a synergistic effect in suppressing cancer cell growth and migration. Additionally, the use of a nanocarrier to deliver the Myc inhibitor prodrug showed improved therapeutic outcomes in animal models. These findings highlight the potential of this novel therapeutic approach for prostate cancer treatment.