Transition state analogue of MTAP extends lifespan of APCMin/+ mice

AbstractA mouse model of human Familial Adenomatous Polyposis responds favorably to pharmacological inhibition of 5′-methylthioadenosine phosphorylase (MTAP). Methylthio-DADMe-Immucillin-A (MTDIA) is an orally available, transition state analogue inhibitor of MTAP. 5′-Methylthioadenosine (MTA), the substrate for MTAP, is formed in polyamine synthesis and is recycled by MTAP to S-adenosyl-l-methionine (SAM) via salvage pathways. MTDIA treatment causes accumulation of MTA, which inhibits growth of human head and neck (FaDu) and lung (H359, A549) cancers in immunocompromised mouse models. We investigated the efficacy of oral MTDIA as an anti-cancer therapeutic for intestinal adenomas in immunocompetent APCMin/+ mice, a murine model of human Familial Adenomatous Polyposis. Tumors in APCMin/+ mice were decreased in size by MTDIA treatment, resulting in markedly improved anemia and doubling of mouse lifespan. Metabolomic analysis of treated mice showed no changes in polyamine, methionine, SAM or ATP levels when compared with control mice but indicated an increase in MTA, the MTAP substrate. Generation of an MTDIA-resistant cell line in culture showed a four-fold amplification of the methionine adenosyl transferase (MAT2A) locus and expression of this enzyme. MAT2A is downstream of MTAP action and catalyzes synthesis of the SAM necessary for methylation reactions. Immunohistochemical analysis of treated mouse intestinal tissue demonstrated a decrease in symmetric dimethylarginine, a PRMT5-catalyzed modification. The anti-cancer effects of MTDIA indicate that increased cellular MTA inhibits PRMT5-mediated methylations resulting in attenuated tumor growth. Oral dosing of MTDIA as monotherapy has potential for delaying the onset and progression of colorectal cancers in Familial Adenomatous Polyposis (FAP) as well as residual duodenal tumors in FAP patients following colectomy. MTDIA causes a physiologic inactivation of MTAP and may also have efficacy in combination with inhibitors of MAT2A or PRMT5, known synthetic-lethal interactions in MTAP−/− cancer cell lines.

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A novel tissue-based ß-catenin gene and immunohistochemical analysis to exclude familial adenomatous polyposis among children with hepatoblastoma tumors

Pediatric Blood & Cancer ◽

10.1002/pbc.26991 ◽

2018 ◽

Vol 65 (6) ◽

pp. e26991 ◽

Cited By ~ 5

Author(s):

Hendrikus J. Dubbink ◽

Iris H.I.M. Hollink ◽

Carolina Avenca Valente ◽

Wenhui Wang ◽

Pengyu Liu ◽

...

Keyword(s):

Familial Adenomatous Polyposis ◽

Immunohistochemical Analysis ◽

Adenomatous Polyposis

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Familial adenomatous polyposis in dogs: hereditary gastrointestinal polyposis in Jack Russell Terriers with germline APC mutations

Carcinogenesis ◽

10.1093/carcin/bgaa045 ◽

2020 ◽

Author(s):

Kyoko Yoshizaki ◽

Akihiro Hirata ◽

Naohito Nishii ◽

Mifumi Kawabe ◽

Minami Goto ◽

...

Keyword(s):

Familial Adenomatous Polyposis ◽

Strong Association ◽

Tumor Development ◽

Immunohistochemical Analysis ◽

Colorectal Polyps ◽

Nuclear Accumulation ◽

Adenomatous Polyposis ◽

Gastrointestinal Polyposis ◽

Hereditary Disorders ◽

Apc Mutations

Abstract Many hereditary disorders in dogs have equivalents in humans and thus attract attention as natural animal models. Breed predisposition to certain diseases often provides promising clues to explore novel hereditary disorders in dogs. Recently, cases of gastrointestinal (GI) polyps in Jack Russell Terriers (JRTs) have increased in Japan. In 21 affected JRTs, polyps were found in either or both the stomach and colorectum, with a predilection for the gastric antrum and rectum. Multiple polyps were found in 13 of 21 examined dogs, including 5 dogs with both gastric and colorectal polyps. Some dogs were found to have GI polyps at an early age, with the youngest case being 2.3 years old. Histopathologically, 43 of 46 GI polyps (93.5%) were diagnosed as adenomas or adenocarcinomas. Immunohistochemical analysis revealed cytoplasmic and nuclear accumulation of β-catenin in the tumor cells. As in the case of human patients with familial adenomatous polyposis, all examined JRTs with GI polyps (n = 21) harbored the identical heterozygous germline APC mutations, represented by a 2-bp substitution (c.[462A>T; 463A>T]). The latter substitution was a non-sense mutation (p.K155X) resulting in a truncated APC protein, thus suggesting a strong association with this cancer-prone disorder. Somatic mutation and loss of the wild-type APC allele were detected in the GI tumors of JRTs, suggesting that biallelic APC inactivation was involved in tumor development. This study demonstrated that despite differences in the disease conditions between human and dog diseases, germline APC mutation confers a predisposition to GI neoplastic polyps in both dogs and humans.

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New platinum(IV) complex with adamantylamine ligand as a promising anti-cancer drug: comparison of in vitro cytotoxic potential towards A2780/cisR cisplatin-resistant cell line within homologous series of platinum(IV) complexes

Anti-Cancer Drugs ◽

10.1097/01.cad.0000127147.57796.e5 ◽

2004 ◽

Vol 15 (5) ◽

pp. 537-543 ◽

Cited By ~ 26

Author(s):

Jaroslav Tur??nek ◽

Andrea Ka??n?? ◽

Dana Z??lusk?? ◽

Ji???? Ne??a ◽

Veronika Kvardov?? ◽

...

Keyword(s):

Cell Line ◽

Homologous Series ◽

Resistant Cell ◽

Resistant Cell Line ◽

Cancer Drug ◽

Cytotoxic Potential ◽

Anti Cancer

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Conversion Therapy Using mFOLFOX6 With Panitumumab for Unresectable Liver Metastases From Multiple Colorectal Cancers With Familial Adenomatous Polyposis

International Surgery ◽

10.9738/intsurg-d-13-00125.1 ◽

2014 ◽

Vol 99 (6) ◽

pp. 795-801 ◽

Cited By ~ 2

Author(s):

Yuji Toiyama ◽

Yasuhiro Inoue ◽

Takahito Kitajima ◽

Masato Okigami ◽

Mikio Kawamura ◽

...

Keyword(s):

Rectal Cancer ◽

Colon Cancer ◽

Familial Adenomatous Polyposis ◽

Liver Metastases ◽

Sigmoid Colon ◽

Immunohistochemical Analysis ◽

Sigmoid Colon Cancer ◽

Colorectal Cancers ◽

Adenomatous Polyposis ◽

Wild Type

Abstract A 39-year-old man received a diagnosis of unresectable multiple liver metastases from multiple colorectal cancers with familial adenomatous polyposis. After construction of an ileostomy, modified FOLFOX6 (mFOLFOX6) with panitumumab was administrated because rectal cancer and sigmoid colon cancer are KRAS wild type. The 13 courses of chemotherapy resulted in a marked reduction in the size of liver metastases and sigmoid colon cancer. Consequently, curative resection with total colectomy, ileal pouch anal anastomosis, and liver metastasis resection with radiofrequency ablation was performed. Progression of KRAS wild-type rectal cancer after chemotherapy suggested that each clone from rectal and sigmoid colon cancer might have a different sensitivity to epidermal growth factor receptor antibody. Immunohistochemical analysis revealed loss of PTEN expression in rectal cancer compared with liver metastases from sigmoid colon cancer, showing that the difference of mFOLFOX6 with panitumumab might be related to activation of the PI3K-AKT pathway.

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