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Research Highlight | May 06, 2022

Re-defining Li-Fraumeni Syndrome: A catchup with Dr. David Malkin, leader of the Terry Fox New Frontiers Program Project Team studying Li-Fraumeni Syndrome

Nearly four years ago, the Terry Fox Research Institute announced it was granting renewal funding to a research team focusing on the early detection and prevention of cancer in patients with Li-Fraumeni Syndrome, a rare genetic disorder that causes almost all those affected to develop cancer at one point or another of their lives.

Over the last four years, the team has made significant findings that better help understand, diagnose, and potentially treat this cancer predisposition syndrome.

We recently caught up with the project’s leader, Dr. David Malkin, a world-renowned pediatric oncologist at the Hospital for Sick Children in Toronto, to learn more about the team’s recent advances. Here’s what he had to say.

What are some of the major findings/advances you've been able to make as part of this iteration of your PPG project?

Several important findings have already emerged from our work.

1) Using new techniques to personalize surveillance methods. During the first iteration of this project, we created the Toronto Protocol, a combination of regular surveillance imaging tests, bloodwork and physical examinations, that helped us prove that early detection of cancer in the context of the Li-Fraumeni Syndrome is associated with improved survival. This protocol, while effective, is not patient-unique: meaning that some patients likely undergo more surveillance than they require, while others may require even closer surveillance.
To address this challenge, we have developed several projects that are searching for a variety of biomarkers in the blood to determine who may need more surveillance[i]. We are moving forward with these projects and anticipate that they will provide a more precise approach to predict both age of onset and tumor type on a patient-specific basis. Thus, our surveillance protocol can be more precisely designed for each unique patient.

2) Improving imaging technology to better diagnose cancer. False positive and false negative reading of whole-body MRI surveillance imaging poses a significant challenge for accurate clinical management decisions in LFS. That’s why we are working to improve imaging accuracy with evolving technical modifications of conventional MRI technology[ii]. This work, coupled with the emerging biomarkers work mentioned above, could make our protocol even more effective, enhancing early tumor detection and improving overall outcomes;

3) Better understanding the genomic landscape of cancer in LFS patients. An important step to developing and introducing effective therapies for patients with LFS who develop cancer is to understand the genomic landscape of these tumors. Over the last few years, we have discovered that genomes of these tumors are different at a molecular level than their sporadic counterparts (for instance, in osteosarcoma[iii] and rhabdomyosarcoma[iv]). This work has also provided evidence to suggest that the critical molecular genomic events that drive malignant transformation of cells in LFS patients occur months – if not years – before they manifest clinically. These findings suggest potential opportunities to explore the use of agents that might prevent these events from happening, and in so doing, significantly reduce cancer risk;

4) Designing clinical trials to test anti-cancer drugs. We are also working with a group of collaborators that using a variety of models of LFS[v] (mouse, zebrafish and skin-derived fibroblast cell lines) to examine the role of various drugs that are known to modify the function of p53, a gene which ordinarily plays a significant role in suppressing tumour growth but that is mutated in LFS patients.
These studies suggest that some of these agents can modify the abnormal function of mutant p53 and lead to delayed tumor onset. These findings form the basis on which to develop clinical trials – which we have already begun doing with colleagues at the National Institutes of Health in the US and Oxford University in the UK;

5) Redefining LFS. The clinical presentation of Li-Fraumeni syndrome and the spectrum of mutations across the TP53 gene are widely heterogeneous. With colleagues in Germany, France and the US, Dr. Malkin led a study that proposes new criteria that define LFS as a spectrum of disease rather than a single ‘syndromic’ entity[vi]. This study will lead to more precise classification of patients leading to more tailored clinical management.

How are these findings helping to advance the science of cancer? 

At least 17% of children with cancer have an underlying genetic predisposition – and the frequency among adults is likely to be similar. However, until quite recently, most of the focus of cancer research and science has been on sporadic cancers.

The findings we have generated to date in the context of LFS – enhanced surveillance techniques, biomarker development, re-definition of the syndrome and strategies for pharmacologic prevention of tumors - form the basis on which similar approaches can be taken for other hereditary cancer syndromes. In fact, the LFS story formed the basis for a series of surveillance guidelines to be developed across over 50 childhood cancers.

What foreseeable impact could these discoveries have on patients

Improved and more precise early tumor detection surveillance strategies will significantly reduce the burden of disease in patients with LFS. In addition, it would reduce the need for unnecessary testing which reduces the inconvenience to families for excess visits to clinic and hospitals. The development of novel approaches to reduce the risk of malignant tumor development would have enormous impact on outcome – and the implementation of a clinical trial to validate the pre-clinical work will be instrumental in realizing this goal.

How has TFRI's PPG award impacted the field of Li-Fraumeni research? 

Our PPG team represents the largest and most scientifically diverse and comprehensive LFS program in the world. We collaborate very closely with numerous other teams around the world on many aspects of the projects we describe and share our data widely and willingly.

The surveillance/early detection studies have already changed the approach to clinical management of LFS patients and their family members. The pre-clinical studies of pharmacologic prevention agents have led to development of clinical trials – to be initiated shortly in the UK and US (a Canadian one that will focus on children has been designed and we are looking for funding opportunities).  Our program is still looked upon by our international colleagues as the paradigm of a multi-disciplinary approach to address this devastating disease.

[i] Paramathas S, Guha T, Pugh TJ, Malkin D, Villani A. Considerations for the use of circulating tumor DNA sequencing as a screening tool in cancer predisposition syndromes. Ped Blood CancerDec;67(12):e28758, 2020.

[ii] Tewattanarat N, Junhasavasdikul T, Panwar S, Joshi S,  Abadeh A, Greer ML, Goldenberg A, Zheng G, Villani A, Malkin D, Doria AS. Diagnostic Accuracy of Imaging Approaches for Early Tumor Detection in Patients with Li-Fraumeni Syndrome. Accepted for publication in Pediatric Radiology.  PRAD-D-21-00155R2

[iii] Diessner BJ, Pankratz N, Hooten AJ, Mirabello L, Sarver AL, Mills LJ, Malkin D, Kelley AC, Spector LG. Nearly half of TP53 germline variants predicted to be pathogenic in patients with osteosarcoma are de novo: a report from the Children’s Oncology Group. JCO Precis Oncol. 2021 Oct; 2;4:PO.20.00087. PMID: 33163847

[iv] Kim J, Light N, Subasri V, Young EL, Wegman-Ostrosky T, Barkauskas DA, Hall D, Lupo PJ, Patidar R, Maese LD, Jones K, Wang M, Tavtigian SV, Wu D, Shlien A, Telfer F, Goldenberg A, Skapek SX, Wei JS, Wen X, Catchpoole D, Hawkins DS, Schiffman JD, Khan J, Malkin D, Stewart DR. Pathogenic germline variants in cancer susceptibility genes in children and young adults with rhabdomyosarcoma. JCO Prec Oncology. 2021, Jan; 5:PO.20.00218. PMID: 34095712

[v] Prykhozhij, S. V., Fuller, C., Steele, S. L., Veinotte, C. J., Razaghi, B., Robitaille, J. M., McMaster, C. R., Shlien, A., Malkin, D., & Berman, J. N. (2018). Optimized knock-in of point mutations in zebrafish using CRISPR/Cas9. Nucleic acids research46(17), e102.

[vi] Kratz CP, Freycon C, Maxwell KN, Nichols KE, Schiffman JD, Evans DG, Achatz MI, Savage SA, Weitzel JN, Garber JE, Hainaut P, Malkin D. Analysis of the Li-Fraumeni Spectrum Based on an International TP53 Variant Dataset. JAMA Oncology. 2021; 7(12): 1800-1805. PMID: 34709361