6.11 Current Research Programs

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There are currently various cancer research programs involving personalized therapy in North America. Most of the research being done on personalized cancer therapy involves analysis of patient tumour samples to find biomarkers of different cancers. This analysis usually only includes genomic sequencing but could also include microarray to test gene expression levels and transcriptome sequencing or proteomics to investigate at the RNA or protein levels. The following will provide a brief overview of ongoing work at both the industrial and acedemic level.

 

 

Genome British Columbia

 

The Personalized Medicine Program at Genome British Columbia is currently funding three projects, including one project on adverse drug reactions, a project on biomarkers in heart and kidney transplant, and a project on the application of genomics to Acute Myeloid Leukemia (AML) (1). The project on AML is currently taking place at BC Cancer Agency in Vancouver, BC, being led by Dr. Aly Karsan and Dr. Marco Marra (2). The aim of this project is to replace current testing methods with a single genomic analysis that will provide physicians with all of the needed information to treat patients according to their specific disease profile (2). The study will analyze the genomes of diseased cells from different patients with AML to try to find and identify specific biomarkers of AML that will be of use in determining the best treatment options of patients (2). By reducing the current testing methods to a single genomic test, not only will it save time and money, but it will reduce patient suffering by reducing the number of tests needed, and by reducing the stress of waiting for the results of multiple tests.

 

Personalized Oncogenomics (POG)

 

One of the many programs funded by the BC Cancer Foundation is the Personalized Onco-Genomics (POG) program localized at the BC Cancer Agency (BCCA) (7). Founded by Dr. Marco Marra (Genome Sciences Center) and Dr. Janessa Laskin (BCCA), the POG project aims for the use of full genome sequencing to identify the specific pathways behind the growth of each patient’s cancer for a personalized treatment tailored with therapies that are specific in targeting the driving pathways (7, 8).

 

The majority of cancers are currently treated on the basis of origin with the aid of retrospective knowledge and experience from previous clinical trials or treatment regimens (7).  However, many cancers—even those stratified into the same subtypes and risk groups—are unique and thus, behave and respond differently to standard chemotherapies that are often expensive and degenerative to the patient’s quality of life (7). The POG project recognizes the heterogeneity of cancers and operates on the basis that effective cancer treatment comes from relevantly targeted therapy (9). The POG program is targeted towards patients who have incurable or advanced stage cancers and whom are willing to consent to fresh tumour biopsies and if available, for release of archival tumours—blood or skin samples are also acquired for comparison to normal DNA (9). Patient samples are genome or transcriptome sequenced to identify genetic signatures indicating mutations in certain oncologic pathways that, ideally, have actionable targets with available targeted therapy (9). The POG team —consisting of a diverse panel of researchers, clinicians, and other experts — gather weekly for group discussion and analysis of each patient’s analysis results and treatment options (9).  Ultimately, the POG project is working towards an extensive database in connecting the genetic signatures for cancer phenotypes to druggable biological pathways and mutations which allows for effective prognostic knowledge to be applied in a personalized approach to cancer therapy (9). 

 

Pediatric POG Project

The pediatric POG project branched out in January 2014 led by Rebecca Deyell, Rod Rassekh, Anna Lee and Chris Dunham. Pediatric oncology is generally an area of unmet medical need as the majority of clinical drug trials focus on adults first leaving a vague unknowns for the safety and efficacy of the drug for use with children. Currently, most pediatric cancer patients are treated with aggressive chemotherapies, which may be highly detrimental to the child’s quality of life, or with palliation chemotherapy. As such, over 20% of pediatric cancer patients end up relapsing or with a refractory disease. As with the POG program, eligibility for the pediatric POG project requires having an incurable cancer and willingness to consent for a new biopsy, blood sample and for the released of archived tissue samples. Participants of the pediatric POG project must also be older than one year old in age as safety and efficacy data from clinical trials only apply to those older than 12 months. As of March 2015, the Pediatric POG project has 15 patients enrolled with informative and actionable findings found for 8 out of 9 patients analyzed. (8) 

 

 

Vanderbilt-Ingram Cancer Center

 

The Vanderbilt-Ingram Cancer Center is located in Nashville, Tennessee and is associated with Vanderbilt Univerity. The concept of this program is similar to that of Genome British Columbia, but this program is an application of the personalized cancer therapy theory to melanoma, breast cancer and non-small cell lung cancer (3). Patients who are eligible and enroll in this program have their tumor cells sequenced and analyzed to determine abnormal genes (3). No additional biopsies or tests are required, as tissue from the original biopsy is used, causing no extra harm to patients (3). Test results become part of the patient's medical record and can be used by physicians to determine the best route of therapy for the patient, including potentially participating in a clinical trial that targets one or more of the genetic mutations found in the patient (3). This program currently only includes melanoma, breat cancer, and non-small cell lung cancer, but will likely include other types of cancers in the future as new gene panels are developed for other cancers.

 

 

MD Anderson Cancer Center

 

The MD Anderson Cancer Center Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy is associated with the University of Texas, located in Houston, Texas. As with the Vanderbilt-Ingram Cancer Center, it implements personalized cancer therapy by analyzing abnormal genes and gene products in a patient's tumor (4). It is one of the larger institutes studying personalized cancer therapy, with research currently occuring on esophageal cancer, glioblastoma, thyroid cancer, head and neck cancer, endometrial cancer, non-small cell lung cancer, laryngeal cancer, melanoma, renal cancer, colorectal cancer, soft-tissue sarcoma, ovarian cancer, breast cancer, bladder cancer, and lymphoma (5). It aims to include not only genomic DNA analysis, but also analysis of RNA, proteomics and metabolomics in the context of the tumour microenvironment and the immune system of the patient (4).

 

The Cancer Genome Atlas

 

TCGA is a joint project between the National Cancer Institute and the National Human Genome Research Institue in the US. The goal of TCGA is to amass sequencing data on cancer genomes, epigenetics, splicing variants, transcriptional profiles and copy number variations, and to make this information available for analysis. This is part of an international effort to identify genetic mutations associated with cancer and to identify potential therapeutic targets. This helps to answer the issue of processing abilities when cancer genome sequencing yields such large amounts of data. One of the findings of the TCGA has been that single mutations, while associated with cancer, are rarely enough to act as the target of personalized therapies (6). Instead, the associated signaling pathways should be examined to determine how gene expression and gene products have been altered.

 

 

References

  1. "Genomics & Health: Personalized Medicine Program." Genome British Columbia (2014). Web. 24 Feb 2014. <http://www.genomebc.ca/opportunities/funding-awarded/genomics-and-health-personalized-medicine-program/>
  2. "Genomics Applied to the Management of Acute Myeloid Leukemia (AML)." Genome British Columbia (2014). Web. 24 Feb 2014. <http://www.genomebc.ca/portfolio/projects/health-projects/genomics-applied-to-the-management-of-acute-myeloid-leukemia-aml/>
  3. "Personalized Cancer Therapy at Vanderbilt-Ingram Cancer Centre." Vanderbilt University (2014). Web. 24 Feb 2014. <http://www.vicc.org/personalized/>
  4. "Institute for Personalized Cancer Therapy." The University of Texas MD Anderson Cancer Center (2014). Web. 24 Feb 2014. <http://www.mdanderson.org/education-and-research/research-at-md-anderson/personalized-advanced-therapy/institute-for-personalized-cancer-therapy/index.html>
  5. "IPCT Seed Funding Award Recipients." The University of Texas MD Anderson Cancer Center (2014). Web. 24 Feb 2014. <http://www.mdanderson.org/education-and-research/research-at-md-anderson/personalized-advanced-therapy/institute-for-personalized-cancer-therapy/research-programs/index.html>
  6. Gonzalez-Angulo, AM, Hennessy BT, Mills GB. 2010. Future of personalized medicine in oncology: a systems biology approach. Journal of Clinical Oncology, 28(16): 2777-83.
  7. “Funding Priorities.” BC Cancer Foundation. Web. 29 Mar 2015. < http://bccancerfoundation.com/your donations-work/funding-priorities>
  8. Rassekh R, Deyell R. 2015. Pediatric Personalized Oncogenomics: Initial Lessons & Outcomes. MEDG 421 Lecture Notes.
  9. “Personalized Oncogenomics (POG) Program of British Columbia.” ClinicalTrials.gov (2015). Web. 29 Mar 2015. <https://clinicaltrials.gov/ct2/show/NCT02155621>