“The challenge will be creating a new class of compounds active against non-kinase gene fusions”

“The challenge will be creating a new class of  compounds active against non-kinase gene fusions”

Dr Timothy Triche M.D., Ph.D., is co-director, Center for Personalized Medicine, Children’s Hospital Los Angeles. Prior to joining CHLA, Dr Triche was Head of Molecular Diagnostics in the Laboratory of Pathology at the National Cancer Institute. He has developed numerous biomarker profiles for cancer diagnosis, prognosis and treatment as a part of the NCI’s initiatives. His focus is on functional characterization of non-coding RNAs in cancer and development.

Dr Triche speaks about how critical personal medicine is in paediatric oncology, in an interview with FM. Edited excerpts:

 

 Compared to adult-onset cancers, targeted therapy approaches to paediatric malignancies are limited. How do you explain the gap?

The primary issue is that cancers in the young are driven by a different mechanism than most adult cancers, so targeted therapies developed for targets commonly found in adult cancers are rarely observed in paediatric cancers. There are, however, some notable exceptions, like the recent experience with a targeted agent directed against the so-called NTRK fusions, which are common in certain paediatric cancers. However, the paediatric age group has responded even better than adult patients, suggesting that when such agents are used in children, the response may well be at least as good, if not better than, that observed in older patients.

 

 In what ways do genomics and the advent of NGS impact the diagnosis and treatment of cancers affecting children?

Genomics and NGS have changed the landscape for paediatric cancer diagnosis, prognosis and treatment across all types of cancer in this age group. It has done this by identifying driver gene defects that also provide specific diagnostic, prognostic and often, therapeutic information obtainable by no other method. In our experience, essentially every newly admitted patient undergoes NGS-based genomic profiling to establish an unequivocal diagnosis, which generally leads to precise evidence of tumour aggressiveness, or prognosis,

and thus clinically useful information that guides therapy choice. In select cases, as noted above, this also leads to the use of very specific targeted agents, as are commonly employed in adult cancers.

 

 Molecular targets are relatively less in paediatric cancers. Do you think it is a major hurdle on the way to develop innovative medicines for childhood cancers? How?

It is important to distinguish between the ‘mutation burden’, or the number of mutations in a given tumour, which are indeed far more numerous in adult cancers, as opposed to occurrence of specific gene drivers, which are at least as common in paediatric cancers. Whereas multiple gene defects may act in concert in adult cancers (which also presents challenges for therapy choice: which of the many is actually driving the tumour?), in paediatric cancer there is almost always one or two obvious gene defects, like gene fusions, where pieces of two normal genes are fused and drive the tumour. The challenge is not the absence of a molecular target; it is that gene fusions, with rare exceptions like the NTRK fusions noted above, are not the type of target most ’targeted’ agents can suppress, as opposed to so-called kinase inhibitors, for example. The challenge will be creating a new class of compounds that are active against these gene fusions. Historically, the development of targeted agents really begins with the development of imatinib, which suppresses the BCR-ABL fusion gene found in chronic myelogenous leukaemia, but which is also a common defect in paediatric acute lymphocytic leukaemia and is widely used in adult and paediatric patients alike. Other gene fusions, in contrast, fall into a different class, and to date, no effective therapies have yet been created for the non-kinase gene fusions. This is an area of unmet need in cancer drug development.

 

 The adverse effects with most of the treatments used to cure cancers in children are lasting. How crucial is molecular medicine/screening in this?

Genomic screening is critically important to the most pressing issue in paediatric oncology, which is to minimise long-term adverse effects of conventional chemotherapy while maintaining or improving current survival rates. Specifically, by identifying patients who are candidates for drugs like imatinib and NTRK inhibitors, conventional chemotherapy can often be avoided. In other cases, if the genomic data indicate the patient has a more or less aggressive type of a particular cancer, unnecessary chemotherapy can be avoided, or in the cases of more aggressive tumours, more intense therapy with improved therapy can be administered.

 

Straight Talk

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