Crazy 8 Initiative Program on Childhood Cancer Predisposition

In 2024, ALSF Crazy 8 Initiative will focus on Childhood Cancer Predisposition and Prevention.

The focus must be on pediatric/adolescent cancer predisposition and should be a consortium of two or more institutions with different areas of research collaborating to integrate their expertise. It is strongly encouraged to have a patient advocate on the team.

The proposals will be judged on innovation, scientific soundness, significance, and the potential for impact on improving the lives of children with cancer.

Focus Areas

• The focus of this award will be on multiple aspects of a single cancer predisposition syndrome, or on a broader area (e.g. surveillance) across a number of different syndromes.
• Five major areas of focus have been identified for this Crazy 8 RFA:
  • New Gene Discovery
    • Knowledge of predisposing genetic/genomic signatures in children could lead to better understanding of the etiology of tumors. Even with the widespread adoption of gene sequencing, there are predisposition syndromes and patients who present with unknown underlying genetic mutations. There is a need to gain insights of novel germline genetic drivers that can be adapted to pediatric oncology care.
    • Topics of interest include, but are not limited to:
      • Identifying epigenetic mechanisms that lead to gene alterations and mutations in childhood cancer predisposition syndromes.
      • Identifying low-penetrance genes that drive childhood cancer predisposition syndromes.
      • Identifying uncommon moderate-penetrance variants in cancer-predisposing syndrome genes.
      • Non typical or atypical variants to known genes of cancer predisposition.
      • Identifying genetic/epigenetic modifiers that impact penetrance of phenotype associated with particular driver gene alterations.
      • Based on real-world phenotype data collection and associated genetic correlations through non-biased sequencing analysis, develop a screening panel for patients with cancer predisposition.
  • Genotype-phenotype correlations
    • Two significant challenges in the field of pediatric cancer predisposition are:
      • to determine what role(s) genes associated with adult onset cancers may play in the pediatric context; and
      • to determine the causal relationship of mutations/variants of variable penetrance on cancer phenotype. Hence there is a need to understand and identify genes with an evidence-based causal relationship with the phenotype.
      • This information can inform patient care and genetic counseling for high-risk families.
    • Topics of interest can include but are not limited to:
      • New associations between genotype and phenotype that can inform on cancer susceptibility.
      • Identification/definition of the role of adult-onset tumor predisposition genes in children/adolescents.
      • Incidence of genetic alterations by germline genetic analysis to identify genetic variants.
      • Correlation between family history and germline genetic analysis data to get prognostic information.
  • Surveillance optimization
    • Surveillance has shown to improve outcomes in Li-Fraumeni Syndrome (LFS) patients with germline TP53 mutations, in patients with constitutional mismatch repair deficiency (CMMRD), and other cancer predisposition disorders. Research that addresses surveillance approaches that will provide standardized guidelines globally is critical.
    • Topics of interest include but are not limited to:
      • Compare the effect of germline sequencing of all childhood cancer predisposition genes vs (targeted) genetic testing based on clinical selection. This will help evaluate current surveillance protocols to determine if what is being done and its frequency is effective (or necessary).
      • Evaluate psychosocial impacts on families and patients on germline sequencing of all childhood cancer predisposition genes vs (targeted) genetic testing based on clinical selection to help develop surveillance optimizations that can be implemented successfully.
      • Develop enhanced surveillance diagnostic modalities that include any of the following: multi-omic liquid biopsies/circulating tumor material; Microbiome profiling; volatile organic compounds (VOC) patterns in breath; enhanced imaging technology that will overcome issues of current modalities that pediatric patients face such as a need for prolonged sedation/anesthesia.
  • Predisposition Models
    • Development of pediatric cancer predisposition models is challenging because pediatric cancers are heterogeneous and occur during the developmental stage and in addition to molecular features the developmental lineage of the cell of origin of the cancer also needs to be taken into consideration.
    • Topics of interest include:
      • Animal models that reflect the cancer predisposition seen in humans with the same genetic change are needed to test novel surveillance approaches and to study prevention.
      • Organoid and other in vitro models that can recapitulate cancer genetic changes and can be used for high throughput mutational analysis to inform on effective personalized therapies.
  • Cancer Prevention
    • In childhood cancer predisposition there is a need to explore novel approaches to prevent or delay cancer initiation, or cancer interception to improve patient outcomes.
    • Topics of interest can include but are not limited to:
      • Development of in vitro/I vivo models of cancer predisposition syndromes to explore novel drug screens to delay or prevent cancer onset.
      • Introduction of biomarkers to complement early phase human studies of pharmacologic prevention in cancer predisposition.

Funding Information

• The requested budget should be in proportion to the scope of the proposed project and its corresponding potential for impact. Depending on the type of project and the size of the team, the requested budget should be in the range of $3-5 million USD over four years.

Eligibility Criteria

• PIs, Co-PIs, and Co-Is must have an MD, PhD, or MD/PhD or equivalent and be appointed as faculty (or equivalent) at an academic institution.
• PIs, Co-PIs, and Co-Is must have a track record of publication and funding productivity that demonstrates that the project can be accomplished by the investigators.
• PIs, Co-PIs, and Co-Is institutions may be based in the United States or abroad, and applicants need not be United States citizens. Funds must be granted to nonprofit institutions or organizations and will be distributed in US dollars.

For more information, visit ALSF.