MAX (MYC Associated Factor X)

The MAX gene is included in several diagnostic gene panels, and endocrinologists should be aware of the associated disorders. The limitations of current knowledge highlight the need for further research to better characterize its clinical features, pathogenesis and management.

Despite multimodal therapy (lanreotide, cabergoline, two debulking surgeries), disease control was achieved only after pasireotide and adjuvant proton therapy. The same variant was found in her father, who had a smaller intrasellar macroadenoma causing acromegaly. This familial observation provides the functional evidence that MAX is a driver in GH-PitNET and a candidate gene for PitNET predisposition.

Our systematic review characterized the tumor spectrum and clinical features of MEN5. While these findings outline the emerging clinical phenotype, further studies are needed to define the epidemiology, penetrance and genotype-phenotype associations of this newly recognized entity.

The present study establishes a new structural framework for understanding the dynamics of MAX and provides a foundation for future structure-based drug design targeting the MYC/MAX axis. Finally, our work offers a strategic blueprint for investigating similarly challenging drug targets.

Loss of MAX staining and the identification of tumor LOH at the MAX locus confirms pituitary adenomas as a component tumor in the emerging MEN5 syndrome due to germline pathogenic MAX variants.

While direct targeting of MYC has proven challenging, recent advances in therapeutic strategies, including MYC-MYC-associated factor X (MAX) dimerization inhibitors, bromodomain and extra terminal domain (BET) and cyclin dependent kinase (CDK) inhibitors, synthetic lethality approaches, and epigenetic modulators, have shown promising results in preclinical and early clinical settings. This review discusses MYC's comprehensive impact on TIME and examines the promising therapeutic strategies of MYC inhibition in enhancing the effectiveness of immunotherapies, supported by recent preclinical and clinical findings.

We also optimized our KL2-236 hit compound to generate a more potent, selective, and durable MYC degrader, KL4-219A. Our results reveal a novel ligandable site within MYC and indicate that certain intrinsically disordered regions within transcription factors, such as MYC, can be interrogated by isomerically unique chiral small molecules, leading to destabilization and degradation.

The present study emphasizes the importance of genetic testing in patients presenting with polydactyly and associated anomalies. These cases support the pathogenicity of the recurrent MAX c.179G>A (p.Arg60Gln) variant and significantly broaden the phenotypic spectrum of polydactyly-macrocephaly syndrome/MAX-related disorder.

Nevertheless, this study demonstrates the potential of a multi-layered computational approach to deepen the understanding of MYC-driven oncogenesis in PCC. By integrating motif discovery, network biology, and interpretable machine learning, the work identifies actionable molecular signatures and critical protein targets, providing a foundation for future experimental validation and the development of targeted therapies in pheochromocytoma as well as other rare cancers.

Our findings suggest that MAX-related PPGLs may be associated with other malignancies, including sarcoma, and support expanding surveillance guidelines to include whole-body imaging for early detection of extra-adrenal tumors. Given the rarity of MAX pathogenic variants, further studies are needed to elucidate the full spectrum of presentation and establish comprehensive evidence-based surveillance strategies.

Following the bilateral adrenalectomy, his hypertension was cured. Annual biochemical screening and 2-yearly MRI imaging to look for recurrence of pheochromocytomas were planned according to international consensus.

Genomic complexity was significantly higher in EMD samples compared to BMA, as evidenced by increased tumor mutational burden and the enrichment of 1q gain/amplifications. These findings highlight the distinct molecular profile of EMD compared to BMA and highlighted the genomically complex and heterogeneous nature of extramedullary tumors.