This month, we’re talking about our understanding of the genetic and molecular mechanisms driving prostate cancer. If we can understand how cancer differs from your body’s normal tissues, we can selectively kill cancer while minimizing damage to normal tissue. As it turns out, this type of research is very difficult.
How can genetic changes cause cancer? How do they determine the biology of the resulting cancer?
Genetic information is stored in DNA. The DNA molecule is like a library filled with instructions for a cell to accomplish various tasks. At any one point, only a small set of the instructions are activated and followed. In normal biology, the instructions activated are appropriate to the task at hand: liver cells activate instructions for liver structure and function; muscle cells activate instructions for muscle structure and function. Normally, these cells’ growth and spread are tightly controlled. If you remove half a liver, the liver regrows to its normal size and then stops. Cancers cells’ growth and spread are no longer controlled. Liver cancer cells grow and spread beyond the liver and, if untreated, kill the patient. How does your body read those DNA instructions? Your body first creates a RNA molecule that is a copy of the instruction. You use this RNA molecule to produce a protein that makes cells change their structure or behavior. Cancer behavior comes from a set of proteins that promotes inappropriate growth and spread. Several mechanisms cause the production of these protein sets. The DNA instruction set itself can change, or mutate. We can detect these mutations in DNA instruction sets through DNA sequencing. DNA sequencing technology has advanced rapidly and costs less then $1,000/sample. If you can get a sufficiently large biopsy of your cancer, we can sequence the DNA. Foundation Medicine is the largest commercial firm offering this service today. Unfortunately, mechanisms not involved in DNA mutation, and therefore not detectable by DNA sequencing, can change that RNA copy. Adding the methyl group to DNA commonly alters RNA copy production and plays an important role in prostate cancer. One approach measures RNA copy production of genes important to prostate cancer biology. Tests like Prolaris and Decipher used in early, organ-confined prostate cancer use this approach. Another approach measures proteins that control prostate cancer behavior or response to treatment. Caris Life Sciences measures the presence or absence of proteins that determine responsiveness to two major prostate cancer chemotherapy drugs called Taxotere (docetaxel) and Paraplatin (carboplatin). All of these tests require a biopsy. It is often difficult to biopsy prostate cancer and especially bone metastases. In advanced prostate cancer, we find cancer DNA in the blood. We can isolate and sequence these cancer DNA fragments to identify mutations in a liquid biopsy. Guardant Health is the most established company in this area. At my clinic, we’ve used the Guardant360 liquid biopsy extensively to identify hormone-resistance mutations, as well as DNA repair mutations that predict for PARP inhibitor response. We are only beginning to apply molecular biology to prostate cancer treatment, but the approach has great promise.