GNE Video: Understanding Biomarkers

Friday Grand Rounds are back, a day early because Jeff just flew in and can't wait to tell us all about Biomarkers. 
So, please settle down in your uncomfortable conference room chairs (don't spill coffee) and let's listen to Jeff Settleman.  Jeff is the Senior Director of Discovery Oncology and Staff Scientist at Genentech, South San Francisco, Calif.  He is going to teach us about biomarkers and their potential for identifying which patients may benefit form certain treatments.

If you sitting in the back row behind a six-foot tall (jerk) third-year graduate student, and can't see a thing on the screen, or can't hear (Thank You(!) ladies on my left discussing happy hour after the talk--Jeff is gonna be there,) don't fret.  Here are the Cliffesque notes, just for you.

• What are biomarkers? Biomarkers are anything that can be measured as an indicator of a biological process; the process could be a normal physiological or disease process, or a response to a drug.  These biomarkers could be as simple as “blood pressure” which indicates an elevated risk of stroke, or specific mutations or gene expressions for cancer cells. 
• How are biomarkers used? Biomarkers help determine the risk of certain cancers, for example, BRCA mutations indicate a higher risk of developing hereditary breast or ovarian cancer.  Other biomarkers tell us about (1) the aggressiveness of a disease, (2) predict patient's response to a particular drug or (3) help match patients with appropriate drugs [personalized medicine.]  Biomarkers may be prognostic or predictive or both. 
• Prognostic biomarkers indicate the likely course of recovery of a patient; how long the patient will survive or what is the likelihood of full recovery.  For example, CML patients with certain immunoglobulin gene mutations tend to live longer than those who lack such mutations.  Predictive biomarkers, on the other hand, help understand the likelihood of responding to a drug; help match patients to certain medicines. 
• How are biomarkers used in cancer drug discovery?  Biomarker discovery research helps understand the basic biology of cancer and also help reveal cellular pathways that may serve as cancer’s Achilles’ heel.  Jeff gave the example of a discovery of activated Hedgehog pathway in Basal Cell Carcinoma (a type of skin cancer.)  As a result of this discovery, several companies now have investigational compounds, targeting Hedgehog signaling in cancer, including GDC-0449 by Genentech. 
• What are the challenges in biomarker research?  Each cancer and drug is unique.  Therefore, all potential biomarkers must be rigorously tested in clinical trials—this is easier said than done, particularly when we are dealing with multiple patient subtypes and only (potentially) a few subsets are likely to respond.  Jeff posed, “how much larger a clinical trial should be to see a statistical difference, if one even exists!”  Will the strategy to exclude patients based on certain biomarkers will also exclude patients who may actually benefit in real-world setting.  Therefore, biomarker research needs to be interpreted carefully and outcome used with a healthy dose of caution—case in point, not all women with BRCA mutations will develop breast or ovarian cancer, whereas, some women without such mutations develop these cancers.   Currently, there is no standard criteria or test to separate these women into the at-risk and not-at-risk populations. 
• In summary, biomarkers are important component of cancer drug discovery, and may help in the goals of personalized medicine—matching patients with best possible available cancer treatment option.

Further information

For a list of Jeff Settleman's publications on PubMed, click here.  His recent publications include:

• Personalized cancer therapy with selective kinase inhibitors: an emerging paradigm in medical oncology. McDermott U, Settleman J. J Clin Oncol. 2009 Nov 20;27(33):5650-9. | PubMed | 
• Cancer: miRNA addiction - depending on life's little things. Dornan D, Settleman J. Curr Biol. 2010 Sep 28;20(18):R812-3. | PubMed | 
• EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Singh A, Settleman J. Oncogene. 2010 Aug 26;29(34):4741-51. Epub 2010 Jun 7. | PubMed | 
• Cell line-based platforms to evaluate the therapeutic efficacy of candidate anticancer agents. Sharma SV, Haber DA, Settleman J. Nat Rev Cancer. 2010 Apr;10(4):241-53. Epub 2010 Mar 19. | PubMed | 
• Discovering tumor suppressor genes through genome-wide copy number analysis. Rothenberg SM, Settleman J. Curr Genomics. 2010 Aug;11(5):297-310. | PubMed | 
• Exploiting the balance between life and death: targeted cancer therapy and "oncogenic shock".
  Sharma SV, Settleman J. Biochem Pharmacol. 2010 Sep 1;80(5):666-73. Epub 2010 Mar 6. | PubMed |

Read Jeff Settleman's profile on ReachMD, LinkedIN and MGH, Boston; he was the Professor of Medicine and Oncology at MGH for 17 years before joining Genentech in 2010.

Closing Statement:  The Cliffesque notes are more or less Jeff's words.  So, if you decide to use it, please cite Jeff's video or Genentech, and not this blog.  See you at the happy hour after the talk!

McDermott, U., & Settleman, J. (2009). Personalized Cancer Therapy With Selective Kinase Inhibitors: An Emerging Paradigm in Medical Oncology Journal of Clinical Oncology, 27 (33), 5650-5659 DOI: 10.1200/JCO.2009.22.9054