In the universe of cancers, there are an overabundance of different types. Not just in terms of where a particular cancer tends to show up (such as ovarian cancers, prostate cancer, etc.), but in how the cancer grows or spreads. In fact, apart from the obvious broader categorization that doctors have assembled over the last century and some smaller, subcategorizations that have happened more recently, it could be argued that every single instance of cancer is as unique as the person who has it. And why wouldn’t that be the case, after all? Every individual person has a unique genetic structure, and cancers are caused by defective genes gone awry, so it stands to reason that each cancer is technically as unique as any one person’s individual DNA.
Of course, there are millions of genes that are virtually identical in everyone…the genes that make my intestines work are probably 99.99% identical to the genes that make your intestines work. That’s just good evolutionary conservation. That also explains why cancers can be categorized at all. In the larger framework of things, our bodies are not so different. The metabolic pathways in me are mostly the same as in everyone else and any single, specific gene in one person will get upregulated or downregulated by the same growth factors as the next person.
However, that uniqueness that encompasses each one of us DOES change something in the equation. It answers (without really answering at all) why treatments respond for with some and adversely for others. It explains why cancer can sometimes be annihilated fairly easily while other times relapsing over and over again.
Compounding that penchant for variety is the problematic approach to screening new therapeutic agents. Typically, new drugs are tested first on in vitro cancer cells that have been propagated extensively over decades. But these same cell lines are far removed from the malignant tumors they are derived from. The development of the soft agar assay did wonders for our ability to study cancer outside of a patient and far removed from the threat of death. However, at the same time, they have created an artificial environment which is non-similar to the complicated mass of tumors, their supportive stromal and hematopoietic cells, and their entire vasculature. This dissimilarity makes for a large drop-off rate between in vitro and in vivo trials, eats up valuable resources and takes time away from patients who need viable options.
More recently, some doctors have grown adept in a procedure called Patient-Derived Xenograft (PDX). In a PDX, a graft of the tumor is transplanted directly into a recipient host; usually an immunocompromised mouse or rat. These PDX are usually transplanted somewhere generic, such as the subcutaneously near the hind quarters of the animal and can more closely recapitulate the biological environment that the tumor required to subsist. Current PDX methods aren’t perfect though. Some cancer varieties, such as breast cancer, are resistant to the act of xenotransplantation for some reason while others, like melanoma or lung, are much easier to graft. Regardless, PDX is providing an excellent opportunity to study and screen potential therapies on a growing variety of cancers, in something very similar to their natural setting.
In late 2011, a group from the John Hopkins University School of Medicine, led by Gary Gallia, managed to successfully transplant Chordoma into athymic mice! All by itself, that was a remarkable achievement. Chordoma is an insidious type of cancer, a bone cancer, but one that only grows in the skull or spinal portions of our body. It forms from remnants of our vestigial notochord and grows slowly and is usually diagnosed only in an adult. It is currently treatable only with surgery to remove the tumor, followed with radiation therapy to deal with what was missed in the surgery. Metastasis occurs in about 20% of patients and the 10 year survival rate is only about 46% with a median survival of patients of 6-7 years.
Then, earlier this month, Gallia’s group trumped their earlier chordoma PDX with a chemotherapeutic inhibition of the chordoma-grafted mice using either erlotinib or gefitinib, two popular EGFR (Epidermal Growth Factor Receptor) inhibitors, demonstrating the efficacy of this approach for chordomas. Overall, they saw a 70-75% reduction in tumor size after nearly double the time post-PDX.
As good as PDX is for replicating cancers in vivo, ultimately it is more useful in an academic setting than a clinical one. It will never produce results fast enough to provide the magic pill that will rid a patient of their immediate cancer. But it is an important step in the research of cancer and one I believe will continue to shed light onto a dark and convoluted metabolic pathway.
Siu, I. M., Ruzevick, J., Zhao, Q., Connis, N., Jiao, Y., Bettegowda, C., & Gallia, G. L. (2013). Erlotinib Inhibits Growth of a Patient-Derived Chordoma Xenograft. PloS one, 8(11), e78895.
Siu, I. M., Salmasi, V., Orr, B. A., Zhao, Q., Binder, Z. A., Tran, C., & Gallia, G. L. (2012). Establishment and characterization of a primary human chordoma xenograft model: Laboratory investigation. Journal of neurosurgery, 116(4), 801-809.
For some additional, informative reading on PDX:
Williams, S. A., Anderson, W. C., Santaguida, M. T., & Dylla, S. J. (2013). Patient-derived xenografts, the cancer stem cell paradigm, and cancer pathobiology in the 21st century. Laboratory Investigation, 93(9), 970-982.
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