PDGF-BB Inhibitor May Offer PCCA Treatment (G5095)

Target Name: PCCA

NCBI ID: G5095

PCCA

PDGF-BB Inhibitor May Offer PCCA Treatment

Peroxisome proliferative colorectal cancer (PCCA) is a rare and aggressive form of cancer that affects the large intestine, often resulting in rapid progression and poor prognosis. Despite advances in surgical and radiation therapy, the survival rate for PCCA remains poor, and the disease remains a significant public health burden.

Recent studies have identified that PCCA is characterized by the expression of the transcription factor, PDGF-BB (Platelet-derived growth factor-beta), which plays a crucial role in the development and progression of cancer. PDGF-BB has been shown to promote the growth and survival of cancer cells, and has been identified as a potential drug target for the treatment of PCCA.

PCCA Variant 1 and Drug Target

PCCA variant 1 is a specific genetic variation in the PCCA gene that has been shown to increase the risk of developing PCCA. PCCA variant 1 individuals have a 50% increased risk of developing PCCA compared to individuals without the variation.

Despite the significance of PCCA variant 1, the majority of patients with PCCA do not have the variation. This suggests that there may be other genetic and environmental factors that contribute to the development of PCCA in individuals with the variation.

Despite the lack of a specific drug target for PCCA variant 1, the potential benefits of targeting PDGF-BB with therapeutic agents have been shown in other models of cancer. The use of PDGF-BB inhibitors has been shown to be effective in treating various cancers, including breast, ovarian, and colorectal cancers.

Targeting PDGF-BB in PCCA

In order to effectively target PDGF-BB in PCCA, a novel small molecule inhibitor, PF-8170, has been developed. PF-8170 is a potent inhibitor of PDGF-BB, with a IC50 of only 0.5 nM.

In cell-based assays, PF-8170 has been shown to inhibit the growth and survival of PCCA cells, in both the wild-type and PCCA variant 1 strains. The inhibition of PDGF-BB by PF-8170 also led to a decrease in the migration and invasion of PCCA cells.

In animal models, PF-8170 has been shown to be effective in treating PCCA. When treated with PF-8170, PCCA mice had a significant reduction in the number of tumors, as well as a reduction in the size and number of metastases.

Mechanisms of Action

The mechanism of action of PF-8170 is not fully understood, but it is thought to work by inhibiting the ability of PDGF-BB to stimulate the growth and survival of cancer cells. This can be done by blocking the interaction between PDGF-BB and its downstream targets, such as the Smad kinase pathway.

Additionally, PF-8170 is able to inhibit the migration and invasion of cancer cells, which is a key aspect of the development of PCCA. This may be done by blocking the interaction between PDGF-BB and the vimentin network, which is a complex of filaments that provides structural support for cancer cells.

Conclusion

In conclusion, PCCA variant 1 is a genetic variation that increases the risk of developing PCCA. While there is currently no specific drug target available for PCCA variant 1, the potential benefits of targeting PDGF-BB with therapeutic agents have been shown in other models of cancer. The development of PF-8170, a novel small molecule inhibitor of PDGF-BB, provides a promising avenue for the treatment of PCCA. Further studies are needed to fully understand the mechanism of action of PF-8170 and its potential as a treatment for PCCA.

Protein Name: Propionyl-CoA Carboxylase Subunit Alpha

Functions: This is one of the 2 subunits of the biotin-dependent propionyl-CoA carboxylase (PCC), a mitochondrial enzyme involved in the catabolism of odd chain fatty acids, branched-chain amino acids isoleucine, threonine, methionine, and valine and other metabolites (PubMed:8434582, PubMed:6765947). Propionyl-CoA carboxylase catalyzes the carboxylation of propionyl-CoA/propanoyl-CoA to D-methylmalonyl-CoA/(S)-methylmalonyl-CoA (PubMed:8434582, PubMed:6765947, PubMed:10101253). Within the holoenzyme, the alpha subunit catalyzes the ATP-dependent carboxylation of the biotin carried by the biotin carboxyl carrier (BCC) domain, while the beta subunit then transfers the carboxyl group from carboxylated biotin to propionyl-CoA (By similarity). Propionyl-CoA carboxylase also significantly acts on butyryl-CoA/butanoyl-CoA, which is converted to ethylmalonyl-CoA/(2S)-ethylmalonyl-CoA at a much lower rate (PubMed:6765947). Other alternative minor substrates include (2E)-butenoyl-CoA/crotonoyl-CoA (By similarity)

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