|
|
October 2007 Volume 1 #3
 Conference offers hope and optimism FISH and CHIPs and prostate cancer Surviving PCa: How exercise can help Reef Knot Award winners • SUBSCRIBE • contact the editor • visit the cpcn website |
FISH and CHIPs and prostate cancer: Refining prognosis and treatment by analysing unique tissue genetics  Men diagnosed with prostate cancer learn pretty quickly to decipher terminology such as T-stage, PSA, and Gleason Score. Why? These words relate to prognosis --- to the medical profession's best guess concerning how a man's prostate cancer will develop and how it should be treated.Research scientists are discovering, developing, or refining prognostic tools each working day, so now a man may receive information not only about the level of prostate-specific antigen (PSA) in his blood but also about how quickly that level is increasing (PSA doubling time). He may know not only that his biopsy shows that he has cancer of a particular stage and grade but also whether the cells of his cancer test positive for Ki-67, which indicates that his tumour is actively growing. But senior research scientist Dr. Robert Bristow looks forward to a future in which specific genes or the novel proteins found in "a patient's blood, urine, or within prostate biopsies ... may help a man choose a therapy based on his unique tissue genetics" --- an individually appropriate, tailor-made treatment. At a presentation to the recent Prostate Cancer Conference 2007, Dr. Bristow, a clinician-scientist at the Princess Margaret Hospital University Health Network, a professor at the University of Toronto, and a senior researcher at the Ontario Cancer Institute, examined some of these up and coming predictive tests, which he suggests "could substantially alter the way that patients and doctors work together to choose the best prostate cancer therapy." His talk, "FISH and CHIPs: Choosing the best prostate cancer therapy for men using individual tissue signatures," discusses some of the new ways that scientists can gather data about genes and their products (i.e., RNA or proteins). One such method, fluorescent in situ hybridization (FISH), uses probes to detect specific features in DNA. "Fluorescent" refers to the technique's use of light to detect these features; "in situ," which means "in place," refers to the fact that the technique is done with chromosomes, cells, or tissues from a specific target site; but the hybridization part is a bit trickier to explain. In simple terms, single-strand nucleic acids (modified DNA or RNA strands) labelled with a fluorescent dye are allowed to interact with the sample genetic material, and hybrids (or complexes) are formed by molecules with sufficiently similar, complementary sequences. The process helps researchers and doctors identify chromosomes and parts of chromosomes, discover chromosome rearrangements, and locate genes on chromosomes. Why might this information be important? It can help us predict the aggressiveness of a man's prostate cancer or whether that cancer will respond to particular treatments. The CHIPs part of Dr. Bristow's presentation informed us about the general usefulness of microarrays (microscopic, ordered sequences of DNA, protein, or tissue), which are presented on a flat surface such as a microchip or a glass slide. These microarrays can give us information about the molecular events involved in prostate cancer, so medical professionals may be able to use them, eventually, to offer a man with prostate cancer a more accurate prognosis and more effective treatments. Bristow lists DNA repair mechanisms, hypoxia, p53, Bax/Bcl-2, EGFR, MDM2, survivin, and p16INK4a as among the most promising prognostic indicators under study through the use of FISH and CHIPs technology. Here are a few of these terms and acronyms explained for the non-scientist. (Please note that, although Dr. Bristow’s talk inspired this article, he is in no way responsible for developing the following explanations.) DNA repair Tissue microarrays can help clinicians and physicians analyse DNA repair processes and proteins within tumour and normal cells. In fact, a major focus of Dr. Bristow's work is to understand how mammalian cells sense and repair double-strand breaks in DNA. 
As he indicated at Prostate Cancer Conference 2007, understanding the relation between DNA repair, or lack of it, and prostate cancer progression may help determine who is at risk of developing prostate cancer, how aggressive a diagnosed prostate cancer is (and how aggressively it should be treated), and which treatments are uniquely appropriate for a particular cancer, given its genetic profile. (The slide is provided courtesy of Dr. Robert Bristow and is from his presentation.)Hypoxia In general terms, hypoxia is a condition in which cells are deprived of an adequate oxygen supply. Cancer cells not only adapt to hypoxia, so tumours can survive and grow in oxygen-deprived environments, they also thrive because hypoxia encourages angiogenesis (the formation of new blood vessels), which is so essential for the growth of tumours. According to Bristow, "cancer hypoxia is linked to increased metastatic spread, chromosomal instability, and resistance to chemo- and radiotherapy." So, by using microarrays to analyse cellular responses to hypoxia and to determine the environment in which prostate cancer cells are growing, researchers may one day be able to improve treatments as well as better predict which treatments are necessary and optimal. p53 The protein p53, a tumour suppressor, helps regulate the cell cycle, and it plays a key role in ensuring that damaged cells are destroyed by apoptosis (cell death). But if p53 has itself mutated and is no longer working as it should, malignant cells can grow unchecked, and the damaged or mutant p53 accumulates. Consequently, mutant p53 may be useful as a biomarker --- a biological indicator --- that a particular prostate cancer is apt to recur or spread. On the flip side, researchers think that, if they can maintain a higher level of properly functioning p53 in prostate cancer cells, they may be able to induce cell death and stabilize a man's prostate cancer. Bcl-2 This protein functions as a blocker of apoptosis (programmed cell death). Research indicates that strong "overexpression of Bcl-2" (meaning finding significantly more than normal amounts of the protein) is associated with high stage, high grade, and metastatic prostate cancer. Bcl-2 has also been associated with the development of androgen-independent prostate cancer, prostate cancer that grows in spite of anti-androgen hormone therapy. Currently, researchers are trying to use Bcl-2 to predict which prostate cancers may be most at risk of progressing to the hormone refractory or androgen-independent stage after treatment. Just to make things even more confusing for the layperson, while Bcl-2 proper is a blocker of cell death, some members of the Bcl-2 family (e.g., Bax, Bak, and Bok) actually encourage cell death. Bax, or Bcl-2-associated X protein, is now being considered in relation to Bcl-2 to determine whether the ratio of Bax to Bcl-2 expression can predict prostate cancer outcomes. EGFR This acronym stands for epidermal growth factor receptor. EGFR is a protein found on the surface of cells, and it binds to EGF (epidermal growth factor). When EGF binds to EGFR, it triggers reactions that cause cells to grow. So it comes as no surprise that EGFR is found at abnormally high levels on the surfaces of many types of cancer cells. EGFR, then, is not only a prognostic marker in prostate cancer but also a potential target for therapy. MDM2 This acronym stands for a gene and for a protein encoded by that gene. MDM2 acts as a negative regulator of p53; in other words, it inhibits the action of p53. So, because p53 is a tumour suppressor and MDM2 inhibits its activity, MDM2 encourages tumour growth and is bad news for men with prostate cancer. In fact, a study by Dr. Alan Pollack found that detectable MDM2 was associated with a doubling of distant cancer spread and a nearly 10 per cent reduction in five-year survival among the 469 men he studied, men who had been treated with radiation and drugs for prostate cancer. Currently, researchers are investigating the value of MDM2 as a target for prostate cancer therapy. Survivin Survivin is also genetic material that inhibits programmed cell death. Although present in the normally developing foetus, it is only detectable in the rapidly growing cells of adults. Consequently, it is frequently seen in cancer cells but almost absent from normal adult cells. High levels of survivin expression in cancer cells seem to indicate aggressive, quickly growing tumours. Again, therapies targeting the effects of survivin may provide novel approaches for the treatment of prostate cancer. p16 In simple terms, p16 is a tumour suppressor, which is frequently deleted or mutated in a wide range of cancers. A recent study on the prognostic value of p16 in locally advanced prostate cancer determined that "low levels of p16 on image analysis appear to be associated with a significantly higher risk of distant metastases among all study patients" and that "p16 expression levels also appear to identify patients with locally advanced prostate cancer with distinct patterns of failure after LTAD [long-term androgen deprivation]." Just to confuse things, the expression of the related p16INK4a appears to increase during prostate cancer progression. According to one study, "because p16INK4a-positive cells were detected only in pre-malignant lesions and carcinomas but not in normal or benign tissues, p16INK4a may aid in the diagnosis of PIN [prostate intraepithelial neoplasia] and prostate cancer in difficult cases." It is hard to imagine what prognostic tests, what treatments, and what terms may become commonplace over the next ten years. Many thanks to Dr. Bristow for alerting prostate cancer survivors to the possibility that the names of specific genes and biomarkers may be as well known in the future as the PSA test is today. |
 www.cpcn.org | cpcn@nexicom.net | Phn: (705) 652-9200 | Fax: (705) 652-0663 Toll Free 1-866-810-CPCN (2726) Toll Free 1-888-322-5735 (français) |