Case study: Finding new therapeutic options for a pediatric osteosarcoma patient

Pediatric cancer cases are challenging, in every sense.  Whenever we take on a new one at Valius, we’re keenly aware of our monumental obligations to both the child and the parents.

We’re also doubly excited when we can help.  

A few weeks ago, we uncovered a promising therapeutic option for a preteen boy with osteosarcoma.  This is the story of how we got there, working in close partnership with his incredible parents and care team.

Patient background

The parents came to Valius a few months ago after their son experienced multiple relapses.  The genetic testing they had performed to date hadn’t uncovered any new treatment options, and their current plan was to continue their son’s existing chemotherapy regimen.  Our team went to work to see if we could help this family find other options.

Our initial findings

We performed our standard diagnostic workup on this patient’s tumor sample, beginning with whole exome (DNA) and whole transcriptome (RNA) sequencing.  

Immediately, we realized that the patient’s sample exhibited high RNA expression of common targets in osteosarcoma, including B7-H3, LRRC15, and FOLR1 (Folate Receptor Alpha), all of which have corresponding therapeutics in clinical trials.  (As a reminder, RNA expression refers to the number of RNA transcripts of each gene in the sample cells; higher RNA expression of a relevant target in tumor cells is correlated with a higher likelihood of therapeutic response.)

Quite quickly, though, we became even more interested in another highly-expressed gene in his sample: PRAME (see chart below).  PRAME is the target of a very promising TCR-T therapy which has demonstrated early clinical efficacy in melanoma, ovarian cancer, and synovial sarcoma.  In fact, one of our previous patients had a complete response to this therapeutic several months ago.

At the RNA level, this patient’s sample exhibited PRAME expression of ~70 transcripts per million, which is higher than in 85% of the solid tumor samples and 84% percent of the sarcoma samples in our database.  Additionally, though the patient’s PRAME expression was low compared to our melanoma cohort (10^th percentile), it was right in line with typical PRAME expression among ovarian cancer samples (49^th percentile).

All of this evidence suggested the patient might be a good candidate for the TCR-T therapy.

(Scientific aside for the interested reader: before we conducted any further analysis, we also confirmed the patient had the necessary HLA type, A*02:01, for this TCR-T therapy to work.)

Confirming our hypotheses

Though an exciting target with an exciting corresponding therapy, PRAME is not commonly detected in or associated with osteosarcomas.  As a result, we thought it especially important to check our work with single-cell RNA sequencing and confirmatory protein staining before bringing any definitive results to the family and their physician.

(As a reminder, single-cell RNA sequencing allows us to separate the tumor cells from the non-tumor, or stromal, cells and analyze them independently. As a result, it can help us understand which targets are specifically expressed in the malignant cells.  For more on single-cell sequencing, you can check out our explainer here.)

Fortunately, single-cell sequencing indicated that PRAME was differentially highly expressed on the patient’s tumor cells rather than the surrounding stromal cells.  See the diagram below, where we’ve plotted a two-dimensional representation of the cells in the patient’s tumor sample; the cells expressing PRAME, which are much more populous in the tumor cluster than outside of it, are colored purple.

Protein staining further demonstrated how widely PRAME was expressed on the patient’s tumor cells, with 95% of the patient’s cells staining positive at moderate intensity.

How we’re helping the family

Before working with us, the parents had no idea their son expressed PRAME highly.  We brought this finding to them and their physician for the first time a few weeks ago and outlined the therapeutic options it might unlock for their son, including the TCR-T therapy.

Recently, we were overjoyed to learn that their physician contacted the therapeutic manufacturer to secure access to the therapeutic, and the manufacturer agreed to support the physician’s application to FDA.

“Valius has provided excellent data for our son and helped us flip the script on osteosarcoma” – patient’s parents

This family’s story isn’t over; far from it.  But it’s certainly taken a turn for the better.

We’re so grateful to work with such persistent, resilient parents, and we thank them for trusting us with their son’s case thus far.  We’re hopeful about this therapeutic option, and ready to continue supporting them on the road ahead.

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