The Game of Battleship and the Battle Against Rare Pediatric Cancers
Alan R. Ehrlich, Chair, Focus on Rhabdo

The game Battleship has been around for almost a century, starting off as a simple, two-player paper and pencil game requiring nothing more than each player drawing a 10x10 grid on piece of paper and positioning their fleet, usually one aircraft carrier, one battleship, one submarine, two destroyers and two PT boats, on the grid by coloring in the boxes representing the warships.

The players would take turns attempting to ‘discover’ the locations of their opponent’s ships. They would call out a grid location (e.g., C-5, F-9) and their opponent would indicate whether they had a hit or miss.

I played the game a lot as a child. Often, to make the game more exciting, we would expand the grid to 20x20, thus expanding the ‘ocean’ from 100 squares to 400. The game took a lot longer to play and scoring a ‘hit’ was far more challenging. Admittedly, expanding the grid made locating the ships and scoring a hit rather frustrating.

Today’s search for cures for rare childhood cancers reminds me a lot of the old Battleship game - only the grid is exponentially larger, there are a large number of players and the stakes involved are the lives of our most vulnerable children. In this highly sophisticated adaptation of the game, rather than calling out the coordinates of a square and getting a hit or miss response, scientists claim their squares by researching a scientific hypothesis with the hope that they will score a hit that will move them one step closer to sinking the ‘cancer’ ship.

Through this scientific discovery process our understanding of these rare pediatric cancers - genomic, biologic, histologic and pharmacologic - has increased tremendously, yet survival amongst metastatic RMS patients has remained both dismal and unimproved over many decades [Brenemen et al., 2003; Malempati and Hawkins, 2012; Williams et al., 2004]. Long-term survival rates for metastatic aRMS and eRMS are <20% and <40% respectively [Breneman et al., 2003; Willams et al., 2004].

While discovery has and continues to provide important insight, by its nature it cannot connect the dots in a way that would provide a complete and accurate picture of the RMS growth - decay - relapse cycle - without which the path to a cure remains both circuitous and distant.

If the Battleship game were played by today’s sophisticated youths, guessing grid coordinates would be replaced by easily obtainable data. The players would be flying drones high above the competition, taking and studying high-definition images laced with GPS data, measuring ocean temperatures, getting local depth soundings and estimating the speed and direction of the local ocean currents. Stealth recon drones would be deployed to track any movement of the fleet and provide information on the number on sailors deployed on each ship and what the mess hall was serving for dinner that night…
…all before a single coordinate was called or a hit or miss response recorded.

Having enough of the right data, correctly analyzing it, and creating and implementing a strategic attack dramatically increases the chance of a successful encounter.

In an article titled “MicroRNA and pediatric tumors: Future perspectives”, published online in Acta Histochemica on 9 March 2015, Galino et al wrote “A better understanding of pediatric tumor biology is needed to allow the development of less toxic and more efficient therapies, as well as to provide novel reliable biomarkers for diagnosis and risk stratification.” [R Gulino, S Forte, R Parenti, L Memeo, M Gulisano, 2015]

With the technological advances that have been made in the last few decades we should have a clear understanding of the tumor biology of even rare pediatric cancers, yet it remains an elusive goal. To gain this understanding we need to move away from the singular use of scientific discovery to a more disciplined and focused “Big Data” approach - creating a database of all relevant patient (and family) information (e.g., DNA, RNA, protein assays, etc.) taken in a consistent manner across the disease progression time-line and then providing grants for a deep analysis of the data.

Would we have a better understanding of the disease if we could analyze the DNA found within the initial tumor to that found outside of the clear margins? The DNA of the initial tumor to that found in the tumor after 4 weeks of chemo? After 20 weeks of chemo? Within the primary tumor area during remission? Against the DNA found in a relapse tumor at the primary site and tumor cells in the metastatic areas? And sadly, but critically important, the DNA from tumor sites and clear sites taken during autopsy should the patient not survive their bout with rhabdo.

Would our understanding of the disease increase if we could do the same for RNA and the various proteins in and around the tumor site(s).

Having this information for, let’s say, 100 RMS patients, would provide a rich database that can be analyzed, synthesized and dissected; various aspects of the disease progression can be compared across multiple patients; and the effects of the disease and the treatment protocol can be analyzed along both the individual’s time-line and a multi-patient time-line - providing a much clearer understanding of the disease pathology.

This certainly opens up a number of ethical, legal, financial and process issues all of which can be answered as we move forward. Most importantly, this singular question must be asked: Are we endangering the lives of those diagnosed with RMS in the future by not aggressively researching all aspects of the disease today, using the only source that we have - the current RMS patients? The data collected would be an incredible gift - given with love and respect - from one generation of patients to those forthcoming.

References:
R Gulino, S Forte, R Parenti, L Memeo, M Gulisano (2015). MicroRNA and pediatric tumors: Future perspectives. - Acta Histochemica

Breneman, J.C., Lyden, E., Pappo, A.S., Link, M.P., Anderson, J.R., Parham, D.M., Qualman, S.J., Wharam, M.D., Donaldson, S.S., Maurer, H.M., et al. (2003) Prognostic factors and clinical outcomes in Rhabdomyosarcoma Study IV. J. Clin Oncol 21, 78-84

Malempati, S., and Hawkins, D.S. (2012). Rhabdomyosarcoma: review of the Children’s Oncology Group (COG) Soft-Tissue Sarcoma Committee experience and rationale for current COG studies. Pediatric Blood & Cancer 59, 5-10

Williams, B.A., Williams, K.M., Doyle, J., Stephens, D., Greenberg, M., Malkin, D., and Pappo, A.S. (2004). Metastatic rhabdomyosarcoma: a retrospective review of patients treated at the hospital for sick children between 1989 and 1999. J Pediatric Hematol Oncol 26, 243-247