HomeENGLISH MAGAZINEFrom gut polyps toward most aggressive cancers: studying magical bullets aiming to...

From gut polyps toward most aggressive cancers: studying magical bullets aiming to erase their root

Sporadic colon cancer is often characterized by mutations in the tumor suppressor gene APC, while autosomal dominant inheritance of a mutant APC allele, as in familial adenomatous polyposis (FAP), results in early-onset massive colonic polyposis that progresses evenly in colorectal cancer unless prophylactic total colectomy is performed. FAP is an inherited condition that causes precancerous polyps to grow in the gut at a young age, often leading to the removal of parts of the colon to prevent cancer. In preclinical experiments a few years ago, researchers at the VCU Massey Cancer Center discovered a new way in which colon cancer develops, as well as a potential “magic bullet” that prevents and treats it. The findings may extend to ovarian, breast, lung, prostate and potentially other cancers that depend on the same growth mechanism.

The researchers targeted the CtBP gene with a drug known as HIPP (2-hydroxy-imino-phenylpyruvic acid) and were able to reduce the development of pre-cancerous polyps by half and restore a normal life to mice born with a predisposition to intestinal polyps analogous to human FAP. In contrast to other cancer-promoting genes, CtBP is not mutated in colon cancer; instead, it is overexpressed to the point where cancer depends on it for growth. CtBP works to reprogram cells by repressing the expression of genes that typically prevent cancer, through a form of cellular suicide known as apoptosis. In the brain, this protein is responsible for the eventual maturation of neurons, preventing them from becoming stem cells again. It simultaneously promotes the expression of other genes that lead to cancer growth and metastasis. The researchers found that CtBP can cause normal human cells to become cancerous when inserted into the cell’s DNA.

In mouse models of familial adenomatosis, HIPP treatment significantly reduced intestinal polyps and increased survival while mice raised without the CtBP gene lived twice as long as those with it. In laboratory experiments, HIPP acted almost like a “magic bullet” to prevent the formation of polyps. The transcriptional co-regulation of CtBP is activated by an increase in the concentration of NADH, an enzyme cofactor derived from vitamin B3 or niacin. Indeed, CtBP is also an enzyme, in which NADH binds to the conserved dehydrogenase domain of CtBP. The dehydrogenase domain of CtBP is addressable by small molecular analogues of its native substrate, α-keto-γ- (methylthio) -butyric acid (MTOB). Of these analogues, 2-hydroxy-imino-3-phenyl-propionic acid (HIPP) and its more potent 4-chloro-derivative (4-CHIPP), antagonize CtBP-driven oncogenic functions. Pharmacological inhibition of CtBP suppresses intestinal polyposis in genetically predisposed mice.

This study is part of a line of research begun in 2010 that investigates CtBP proteins, since in addition to CtBP there is the CtBP2 isoform. The above data can be used against still lethal malignant tumors. In 2019, the research team extended pancreatic cancer trials. The researchers proved that in this type of tumor it is precisely the isoform 2 that predominates in the processes of gene modulation, instead of CtBP1 and the oncogene c-Myc could be an important downstream effector of CtBP2, given that the mutation or gene amplification of c-Myc is present in pancreatic cancer, as well as in breast or colon cancer. When the scientists treated the tumor mice with 4-CHIPP they observed a reduction in tumor masses. The effect was amplified with the simultaneous administration of gemcitabine, a chemotherapy drug used routinely to treat this type of cancer.

Instead, researchers at the University of Texas MD Anderson Cancer Center have developed a new targeted therapy, called POMHEX, that blocks critical metabolic pathways in cancer cells with specific genetic defects. Preclinical studies have found that the enolase inhibitor is effective in killing brain cancer cells that lack ENO1, one of the two genes that encode the enzyme enolase. Enolase is an essential enzyme involved in glycolysis, a glucose metabolic pathway that is elevated in many cancers to fuel cell replication. Two genes, ENO1 and ENO2, encode slightly different but redundant versions of the enolase, and several tumors, such as glioblastoma, lack the ENO1 gene due to chromosomal loss. This leaves the cancer cells with only ENO2 to continue glycolysis, making them highly sensitive to enolase inhibitors. The specific targeting of ENO2 is of interest because it allows for the selective treatment of ENO1-missing tumor cells.

The research team then worked to generate an enolase inhibitor, called HEX, which preferentially targets ENO2 over ENO1. To improve the drug’s ability to enter cells, the team created the prodrug POMHEX, which is biologically inactive until it is metabolized into HEX within the cells. ENO1 deletions also occur in liver cancer, large cell neuroendocrine lung cancers, and biliary tract cancers, all of which share a poor prognosis and poor therapy options. Therefore, once an optimal therapeutic candidate has been developed, the possibility exists to evaluate the ENO2 inhibitor in the treatment of patients with multiple types of cancer. A similar situation occurred for another cellular protein called hypoxia transcription factor (HIF-1alpha). But there is also its HIF-2 counterpart. They are both sensitive to oxygen deficiency and in fact serve the body’s tissues to adapt to conditions of poor oxygen availability.

The lung is a common site for metastases for many cancers. Although breast cancer is often associated with bone metastases, the triple negative, one of the more aggressive types, actually spreads more frequently to soft tissues such as lungs, brain and liver. A couple of years ago, scientists saw that when HIF-1a was absent in the endothelial cells of mice, they developed fewer lung cancers. Interestingly, the opposite was true when they lacked HIF-2a, and they developed many more. In particular, in endothelial cells, HIF-2a is usually present to maintain the stability of the capillary networks, so removing it from these cells is not beneficial in the context of tumor metastases. The inhibitors available for HIF-1a do not discriminate between it and its “cousin” HIF-2a; but very recently some specific ones have been elaborated. For example, the inhibitor MK-6482 (belzutifan) has shown significant efficacy in renal, cerebellar and pancreatic cancers related to VHL syndrome.

The drug demonstrated an acceptable safety profile. Another inhibitor still under study was pre-named PT2385. Scientists evaluated the effect of this HIF2a antagonist at different stages of tumor development to identify genes differentially expressed during treatment. By comparing the way to disable HIF-2 alpha with this drug or in a genetic way, they found that PT2385 did not reduce cell proliferation or clonogenicity but, contrary to the genetic method, it did reduce cell invasion in vitro. This does not appear to occur when cancer cells carry the G323E mutation in HIF2a, which interferes with drug binding and precludes dissociation of the HIF-2 complex. Therefore the drug could be useful at least in cases of kidney cancer that depend on genetic syndromes bearing specific mutations, which today are possible to identify through biopsy and genetic screening.

As you can see, research does not stop at all and least of all can afford it in the fight against cancer, where the therapeutic innovations of the last 20 years have made it possible to extend survival, improve the quality of life and obtain posthumous information to be applied for a personalized modality of therapy.

  • edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Dhawan A et al. CNS Oncol. 2022 Jul; 11(3):CNS91. 

Choueiri TK et al. Nature Med. 2021; 27(5):802-805. 

Hasanov E et al. Expert Opin Investig Drugs 2021; 30(5):495. 

Arnaiz E, Miar A et al. BMC Cancer. 2021; 21(1):896. 

Chawla AT et al. Oncotarget. 2018; 9(65):32408.

Dcona MM et al. Cancer Biol Ther. 2017; 18(6):379.

Korwar S, et al. Bioorg Med Chem. 2016; 24:2707.

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento enzimaticamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (Leader of the R&D for the partnership CoFood s.r.l.) - Autore di articoli su informazione medica e salute sul sito www.medicomunicare.it (Medical/health information on website) - Autore di corsi ECM FAD pubblicizzati sul sito www.salutesicilia.it
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