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SU2C-KWF Translational Research Team Progress Update

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The SU2C-KWF Translational Research Team Progress Update

Prospective Use of DNA-guided Personalized Cancer Treatment

Funding: $1,200,000

Leader: Emile E. Voest, M.D., Ph.D., Netherlands Cancer Institute (NKI), Amsterdam
Co-Leader: René Bernards, Ph.D., Netherlands Cancer Institute (NKI), Amsterdam

Fast Facts on Colorectal and Breast Cancer:

  • In the United States, colorectal cancer is the third most commonly diagnosed cancer and the third leading cause of cancer-related deaths.
  • Colorectal cancer rates are highest in African American men and women and lowest in Asian/Pacific Islander men and women.
  • Excluding cancers of the skin, breast cancer is the most common cancer among US women, accounting for 29% of newly diagnosed cancers.
  • There are nearly 3 million women living in the United States with a history of invasive breast cancer.
  • Because of improved treatments and detection, the overall 5-year relative survival rate for breast cancer has increased from about 75% in 1975 to 90%.

Fast Facts on Prevention Tips:

  • Screening is key to colorectal cancer prevention and is recommended for men and women beginning at age 50.
  • Adopt a physically active lifestyle, and maintain a healthy weight throughout life.
  • Consume a healthy diet with an emphasis on plant sources. Limit your consumption of processed and red meats, as well as alcoholic beverages.
  • Exercising four or more hours a week may lower breast cancer risk, especially for premenopausal women of normal or low weight.
  • Having one first-degree relative (mother or sister) with breast cancer doubles the risk of developing the disease. Consult your healthcare provider to assess your risks.
  • Drinking alcohol has been shown to increase the risk of breast cancer. The risk rises with the amount of alcohol consumed.


Project Background

The International Translational Cancer Team’s Research Project

The concept of personalized medicine refers to the notion that information about the biological make- up of a patient’s tumor can help select the best treatment for that particular patient. Lessons learned from a decade of research have taught us that even though tumors may appear similar under the microscope they are in fact very different at the biological level. Breast tumors, for instance, can vary greatly in the genetic changes (mutations) they carry in their DNA. Scientists now believe that these differences may largely explain our limited success in the treatment of cancer. The promise of personalized medicine lies in the fact that these mutations can be used to predict the response of a patient to anti-cancer drugs, and hence guide the choice of the most appropriate drug for each patient.

The Translation Team is focusing on patients from clinical studies of breast, colorectal, lung, and pancreatic cancer. The Team will collect DNA from these patients’ tumors before and after treatment with anti-cancer drugs. They will then determine if the genetic changes in the tumors impact the patients’ response to the drugs. Armed with this information, they will use state-of-the-art computational biology methods to generate DNA “profiles” that will predict whether patients will respond to a given treatment. By discovering how mutations in tumor DNA are linked to responses to anti-cancer drugs, the Team hopes to be able to make far better educated choices for the treatment for individual patients, leading to greater therapeutic benefit, while at the same time reducing the toxicity of non-effective cancer drugs.

The outcome of this project will have an impact at multiple levels of clinical cancer care. First, it will generate novel tools for analysis of DNA to better select cancer patients for specific treatments. Second, it will speed up cancer drug development by providing ways to match the right patient to the right drug. Third, it will show the value of tumor assessments before and after treatment to understand how the tumors’ biology changes when drug resistance occurs. But most importantly, it will contribute to increased cancer survival and quality of life by helping to deliver the most effective drug to the patient early on, while reducing the toxicity of ineffective drugs.

Status Update:

6-month milestones
During the first 6 months, the Team has obtained approval of the protocol for a clinical trial testing a combination of the drug LGX818 (an inhibitor of the BRAF kinase) and cetuximab (an antibody that blocks receptors for epidermal growth factor) or LGX818 + the drug BYL719 (an inhibitor of the PI3K pathway) and cetuximab in patients with BRAF-mutant metastatic colorectal cancer. The first 6 patients have been included and samples are collected en sequenced.

There was a delay in obtaining the DNA samples from the I-SPY2 study (a clinical trial for women with newly diagnosed locally advanced breast cancer) for sequencing, but the issues have been resolved and the Team expects to start sequencing in the second half of 2013.

The Team has also started to use data from the genomes sequences derived from multiples cancerous cell lines to begin to develop a drug sensitivity model. This model, once validated, will be used to predict whether patients will respond to a given treatment.

12-month milestones
At the end of the first year, the Team has received 26 pairs of samples from the I-SPY2 trial (on December 6, 2013), and started sequencing immediately. They expect the first data to be available at the end of January 2014.

18-month milestones
In the 12-18 month period of the grant, the Team received another 43 pairs of samples from the I-SPY 2 breast cancer study, with an additional 60 pairs expected in June 2014. Sequencing and analysis is underway. The Team also received samples from trials of the drugs cetuximab versus panitumumab (antibodies that block receptors for epidermal growth factor) and trials of cetuximab plus LGX818 (an inhibitor of the BRAF kinase) versus cetuximab plus LGX818 plus the drug BYL719 (an inhibitor of the PI3K pathway) in patients with BRAF-mutant metastatic colorectal cancer.

24-month milestones
In the 18-24 month period of the grant the team reports the following:

  • They have completed the first round of analysis of I-SPY2 breast cancer study samples (130 patients). Although not definitive, there are some clues about mutations that might be linked to resistance or sensitivity to the combination of chemotherapy and neratinib.
  • The I-SPY2 data will now be used a biological “tool box” to refine patient selection criteria for individualized treatment.
  • The Team is accruing patients at the expected rate to their dual and triple combination trial in colorectal cancer (dual: cetuximab (blocks receptors for epidermal growth factor) plus LGX818 (BRAF kinase inhibitor); triple: addition of BYL719 (an inhibitor of the PI3K pathway)). Preliminary data shows excellent safety and a very promising 90% response rate in patients of dual or triple combination. Sequencing of samples is underway.
  • Recruitment to their trial of single treatment with epidermal growth factor receptor inhibitors (cetuximab versus panitumumab) in colorectal cancer is slower than expected, but they have increased the number of clinical trial sites to help increase the number of patients enrolling.
  • The team has added analysis of samples from a 4th trial, testing combination of PD0325901 (an inhibitor of MEK) and dacomitinib (blocks receptors for epidermal growth factor).

30-month milestones
In the 25-30 month period the Team reports continued progress:

  • They have identified a new possible lead that might help understand why women with breast cancer respond to the drug neratibin.
  • They have continued to collect patient samples from three clinical trials that include advanced colorectal cancer, non-small cell lung cancer, and pancreatic cancer for analysis of how the tumors’ biological make-up correlates with response to different drug combinations.
  • With accrual of more patients to the trial, the dual combination of encorafenib (LGX818; a BRAF inhibitor), and the epidermal growth factor receptor inhibitor cetuximab, with or without the addition of BYL719 (a PI3K inhibitor), continues to show significant anti-tumor activity in advanced BRAF mutant colorectal cancer.
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