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About The skanner. (Portland, Or.) 1975-2014 | View Entire Issue (Oct. 11, 2017)
Page 10 The Skanner October 11, 2017 News Treatment cont’d from pg 9 course. This is called “preci- sion medicine,” and it has had some successes in breast cancer treatment. Many biomarker-based, or precision, therapies are now standard of care. But this field needs to be expanded further to improve overall patient outcomes. Not only are tumors are different from one another, but there can even be genetic differ- ences within a single tumor. These differenc- es between tumors and within them are called tumor heterogeneity. Our lab at Michigan State University, under the direction of Eran An- drechek, is studying how best to define the tumor heterogeneity and the effect that these differ- ences have on a patient’s Jonathan Rennhack, pictured here, is part of a team of researchers focusing on identifying biomarkers in breast cancer tumors. response to therapy. In particular, we are using next-generation technol- ogies to understand tu- mor heterogeneity and define better treatment strategies for patients. Tumor diversity makes treatment complexTo devise a better treat- ment strategy we have to understand how het- erogeneity within and between tumors arise in the first place. Tumors are a result of uncontrolled division of a single cell. However, a tumor is not the same throughout. Even though it starts with a single cell, the cells that make up the tumor are not all identi- cal. As a tumor cell divides, each daughter cell has mutations not present in the parent cell. This is called genetic instability. This multitude of muta- tions leads to a surviv- al-of-the-fittest scenario within the tumor (this is called selective pres- sure). Some of these muta- tions give cells an edge over other cells. Selec- tive pressure means that cells with certain characteristics “win” the survival of fittest battle within the tumor. The result is that different “neighborhoods” of the tumor will be populated with clones of the fittest cells. Perhaps one region of the tumor is low in nutrients; it will contain cells that have picked up mutations to survive in a low nutrient environ- ment. Another region might be under constant exposure to the body’s immune system; it will contain cells with im- mune evasion mutations. This is how differences within tumors emerge, and this diversity is also one reason why each pa- tient’s tumor is unique, and subsequently why their tumor’s vulnera- bility to therapy is differ- ent, too. This genomic instabili- ty also exists between pa- tients. A combination of random chance and dif- ferences in the genome lead to unique tumors to develop in each patient. Let’s say, for example, that we are looking at a group of breast cancer patients whose tumors all have the same bio- marker. Some patients have a complete response to a particular treatment tai- lored to that biomarker, meaning that the tumor shrinks and the patient is in remission. “ [Precision medicine] needs to be expand- ed further to improve overall patient outcomes. But one treatment does not fit all patients with the same biomarker. For instance, other patients with that same biomark- er may respond to the same treatment at first, but then their tumor grows back because it has become resistant to the original therapy. This is due to what is called in- tra-tumor heterogeneity, which refers to genetic differences within the tumor, thanks to the ge- netic instability and sur- vival of the fittest that we described earlier. One region of a tumor may have one genetic change, while other regions of the tumor have a differ- ent change. This leads to one region of a tumor re- sponding to a treatment while another region of the tumor will not. Other patients may have little or no response to the treatment that led to remission in patients with the same biomarker, or at least worked initial- ly in other patients. For instance, we have found that the same genes give the tumor different char- acteristics in two differ- ent subtypes of breast cancer (basal and HER2 positive). The difference between tumors from one patient to another, inter-tumor heterogene- ity, is a complicating fac- tor in our current cancer treatment therapy based upon biomarkers. Therefore, the genetic heterogeneity both be- tween tumors and within tumors is a critical factor to be considered in de- veloping suitable treat- ments. Sequencing tumors to find better treatmentsIn the Andrechek lab we have used whole genome sequencing and microar- ray technology chip for examining gene expres- sion data, to understand what the genomic profile of different regions of the tumor look like. We can look at mu- tations, changes in the number of copies of certain genes or trans- location, which is when genes aren’t in the place they should be. Perhaps more impor- tantly, we have worked to understand the impact of those mutations on all of the genes produced by a tumor cell, called the transcriptome. This is important be- cause the transcriptome contains the majority of the instructions the tu- mor needs to grow and survive. We noted that disrup- tion of the expression of one particular gene promotes the forma- tion of tumors as well as slows the tumor growth in a model of breast can- cer. The combination of genes that a tumor takes advantage of to grow are referred to as key onco- genic pathways. If we can profile these pathways and identify which ones are active in a tumor, that could let us design individualized therapies to target them. Our results showed that through the use of target- ed genomic therapy, we inhibited tumor growth in each group. Then we expanded our study to analyze more than 1,000 tumors from breast cancer patients, and we noticed significant shrinkage of tumors. In these trials, we are also able to understand in- tra-tumor heterogeneity through profiling the genetic changes after treatments. This showed the selective pressures a treatment creates on the different types of cells in a tumor.
