Principal Investigators: Kenneth Pienta, MD (Johns Hopkins University)

Co-Investigators: Sarah Amend, PhD (Johns Hopkins University), Angelo De Marzo, MD, Ph.D (Johns Hopkins University), Peter Kuhn, PhD (University of Southern California), James Hicks, PhD (University of Southern California)

Description:

• Once prostate cancer metastasizes, it is incurable and lethal. Each year, more than 29,000 men in the United States die from metastatic prostate cancer. New therapies to prevent and treat metastatic prostate cancer remain an urgent medical need.
• Dr. Kenneth Pienta and team are studying the mechanisms and processes of prostate cancer metastasis.
• Tumor metastasis is a complex process, and studying tumor cell migration alone is insufficient to understand the nuances of cancer spread. A diaspora (from the Greek diaspora meaning “scattering” or dispersion”) is the movement, migration, or scattering of people away from an established homeland. Dr. Pienta and team are using the concept of diaspora to describe cancer metastasis in terms of the forces which cause cancer cells to leave the primary tumor, as well as the environmental and cellular features (“seed and soil”) necessary in a new body site for a metastatic tumor to “take root” and grow there.
• The team previously identified the existence of Poly-Aneuploid Cancer Cells (PACCs) as a subset of circulating tumor cells (CTCs) that appear to be the critical cells that are actually able to metastasize: the majority of CTCs simply do not survive once they leave the prostate. PACCs are large, have high genomic content, and have increased capacity to migrate. PACCs live among the greater cancer cell population, but when the tumor experiences stress (such as hypoxia or treatment with chemotherapy, radiation therapy, or hormonal therapy), PACCs protect themselves by going into hibernation and stopping cell division. The therapy wipes out the dividing cells, but once the treatment is stopped, PACCs wake up and act as stem cells to spawn a new generation of “daughter” cancer cells. Interestingly, hibernating PACCs have somehow developed resistance to that therapy, which is passed on to the new daughter cells.
• In this project, the team will determine the numbers and biology of PACCs in prostate cancer tissues from patients at different clinical disease states.
• The team will validate that the development of therapeutic resistance in PACCs occurs through mechanisms of reversible quiescence (hibernation).
• The team will study the mechanisms and functional consequences by which PACCs undergo whole genome doubling, and reversibly leave the cell cycle, and then reenter the cell cycle when stress is removed, to repopulate the tumor cell population.
• If successful, this project will determine the biology of a major mechanism underlying tumor metastasis and therapeutic resistance.

What this means to patients: Dr. Pienta and team are investigating the mechanisms by which a novel, giant tumor cell subtype, Poly-Aneuploid Cancer Cells (PACCs), are able to act as the major cell type seeding prostate cancer metastasis and therapeutic resistance. This may lead to the identification of new therapeutic strategies for preventing prostate cancer progression, treatment resistance, and metastasis.