Curing Cancer: Lessons from a Prototype

SIMPLE SUMMARY: Germ cell tumor of the testis (TGCT) teaches us that to cure cancer, we need to acquire and apply proper biological insight and clinical acumen. In 1946, about 90% of patients with metastatic TGCT died within the first year of diagnosis. Today, over 90% of the same patients are curable. This complete reversal in the cure rate of TGCT is not because we have designed better drugs (we have not), but because we have learned how to use the same drugs in the right patients under the right settings. Importantly, TGCT is a prototype stem cell tumor that may hold the key to unlocking the origin of cancers, thereby enhancing our understanding of cancer and improving the cure and care of patients with cancer. ABSTRACT: Germ cell tumor of the testis (TGCT) is a remarkably curable solid tumor even when it is widely metastatic and patently heterogeneous. It provides invaluable clues about the origin and nature of metastasis and heterogeneity, cancer dormancy and late recurrence, drug sensitivity and resistance, tumor immunity, and spontaneous remission that would enable us to enhance the cure and improve the care of patients with other currently intractable solid tumors. After all, germ cells are primeval stem cells and TGCT are a perfect stem cell tumor for us to investigate a stem cell versus genetic origin of cancer. In many respects, TGCT is a prototype stem cell tumor that will enable us to elucidate the role of differentiation versus dedifferentiation in the evolution of a complex mixed tumor. It will help us decipher relevance of the genome versus the epi-genome in a progenitor cancer stem cell versus a progeny differentiated cancer cell. Importantly, clarification of a cellular context versus the genetic makeup in cancer has immense clinical implications. We postulate a unified theory of cancer derived from seminal TGCT research to improve personalized cancer care. Contrary to current norms and conventional wisdom, we propose that when it concerns a complex rather than simple cancer and a mixed rather than pure tumor (which is practically all solid tumors) multimodal therapy trumps targeted therapy and integrated medicine overrides precision medicine.