SU2C-Dutch Cancer Society Translational Cancer Research Dream Team Progress Update
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SU2C-Dutch Cancer Society Translational Cancer Research Dream Team Progress Report
Tumor organoids: a new pre-clinical model for drug sensitivity analysis
Leader: Hans Clevers, MD, PhD, Hubrecht Institute of Developmental Biology and Stem Cell Research
Co-Leader: Johannes L. Bos, PhD, University Medical Center (UMC) Utrecht
Fast Facts on Organoids:
- Organoids (“organs in a dish”) are grown from small samples of cells taken from normal healthy tissue or tumors
- Organoids can be grown in the laboratory for long periods of time and can be used to study patients’ tumors outside the body
- Organoids can be used to profile the genetic make-up of the individual patient’s tumor and to test how well anti-cancer drugs work
Cancer is caused by changes in the genetic material, or DNA, of normal cells. These changes accumulate over time, first turning normal cells into precancerous cells and then into cancer cells. Recent technological advances have made it possible to determine all of the DNA changes that have occurred in an established, malignant tumor. This knowledge helps doctors to understand how cancers arise and grow, and to identify the treatments that may be most effective.
The promise of “precision medicine” lies in the ability of researchers to devise treatment approaches that are specific to the genetic profile of individual patients and their tumors. However, predicting which drug, or drug combinations, will be the most effective based on the genetic makeup of a tumor remains a challenge. This is largely because for most DNA changes, it is not known how they contribute to the cancer process or how they can be targeted by drugs. Therefore, there is an urgent need for new tools and technologies to investigate the consequence of all these DNA changes.
This SU2C-Dutch Cancer Society Dream Team has developed a groundbreaking technology that allows tumor samples isolated from patients to be maintained and grown in a laboratory setting. These growing tumors, which are called “tumor organoids,” provide an unprecedented opportunity to combine DNA sequence analyses with functional studies of tumors from individual patients. Importantly, these tumor organoids will allow studies of sensitivity and resistance to a large number of anticancer drugs in the lab. The ultimate goal of this Dream Team is to identify the best anti-cancer drugs in the laboratory, before treating the patient, to optimize patient benefit.
To achieve their goal, the Dream Team will establish a novel, genetically diverse ‘living biobank’ of tumor organoids to test new cancer drugs as a first step toward tailored clinical trials. The team is focusing on patients with colon, pancreatic, or breast cancer with plans to develop organoids of normal and tumor samples from 80 patients with each cancer type. They are also working to optimize the technology for prostate tumors. After determining the DNA sequence of each of these organoids, the researchers will test their sensitivity to 100 different drugs. Armed with this knowledge, the Dream Team will be able to classify tumors based on the drug sensitivity of tumor organoids and devise rules to match specific treatments with defined DNA changes in tumors. The team will then use this knowledge to perform additional preclinical studies of novel therapeutic strategies, including drug combinations.
By performing more thorough preclinical studies facilitated by this new technology, the Dream Team hopes to design novel, sophisticated clinical trials that will test treatment regimens tailored to a patient’s tumor. If successful, this Dream Team project has the potential to provide a true paradigm shift in drug development, clinical trial design, and therapy.
During the first 6 months, this Sta Op Tegen Kanker Dream Team has laid the foundation for executing their proposed studies. They have:
- Established the infrastructure for building the living biobank
- Established a >95% success rate for growing colon cancer organoids and have a bank of 22 colon cancer organoids, from 20 patients, along with healthy colon tissue from the same patients for comparison
- Established the method for growing pancreas cancer organoids, and have successfully established 10 out of 11 pancreas cancer organoids
- Optimized the method for growing prostate cancer organoids, although the success rate is lower than colon or pancreas cancer
- Established that tumor organoids contain the genetic features and diversity of the original tumor
- Initiated tests for anti-cancer drug responses using tumor organoids
By the end of their first year, the Dream Team plans to continue growing the colon and pancreas biobank, followed by DNA sequence analysis and drug profiling, toward their goal of 80 normal-tumor organoid pairs (tumor and normal from the same patient) for each organ. They hope to improve the efficiency of prostate cancer organoid generation so that the endpoint of 80 normal-tumor prostate organoid pairs can be established as planned.
In the 7-12 month period of funding the Dream Team reports significant progress in building the biobank and the results of their first drug screens:
- The biobank has expanded to 67 normal-tumor pairs of organoids from colon and 22 pairs from pancreas. The Dream Team reports a high success rate in growing colon and pancreas organoids and a steady supply of samples from collaborating hospitals.
- They have successfully established the process for growing prostate organoids from lymph node metastases and report three samples in the biobank.
- Using the first 20 colorectal tumor organoids, the Dream Team has screened a panel of 83 drugs, which includes drugs in clinical use, drugs being tested in clinical trials, and new experimental drugs. They found a range of responses to the drugs – some organoids respond very well to certain drugs and others respond poorly – and are working now to understand the biological reason for the individual tumor organoid response to specific drugs.
During the next 6 months, the Dream Team will continue the advancement of their five clinical trials. Biomarker assays on human specimens will be tested and the samples will ultimately be conducted in batches. The Computational Biology group will continue to work on supporting all groups and pilot their data software for sharing information.
In the next 6 months the Dream Team will continue to build the biobank, genetically characterize each organoid, and screen for the most effective drugs.
In the 13-18 month period of funding the Dream Team has continued to build their organoid biobanks and made significant progress in developing their drug screening platform:
- The colon cancer tumor organoid biobank has been expanded to 86 tumor organoids, many of which are paired with normal colon tissue for comparison. Nine colon cancer metastases are included in the biobank.
- The pancreas tumor biobank remains at 20 organoids. Continuing challenges have been encountered in growing prostate cancer organoids. On the advice of the SU2C Review Team, the Dream Team has moved the emphasis to breast cancer, although efforts to optimize the prostate tumor organoid approach will continue. Currently 33 breast cancer tumor organoids have been established.
- The Dream Team has established good reproducibility in their initial drug screening work. They are working to miniaturize the process further so that they can increase the speed and capacity of their drug screening pipeline.
The Dream Team has sufficient numbers of both colon and breast cancer organoids to start the drug screening and genetic characterization at the required scale. The first results are expected in the next 6 months.
In the 19-24 month period of funding the Dream Team reports continued progress on their work building tumor organoid biobanks. Their drug profiling efforts are lagging behind but are moving forward:
- The colon cancer and breast cancer tumor organoid biobanks are complete with 80 or more organoids in each.
- The pancreatic cancer tumor organoid biobank remains at 20. The Dream Team is considering reducing their goal of 80 for this biobank so that they can instead study differences between organoids derived from the same tumor (heterogeneity).
- The Dream Team has decided to limit the number of normal (non-cancerous) organoids they include in the biobanks because they have found that there is not as much to be gained from these studies as they originally expected.
- The Dream Team has made some potentially important discoveries about mutant K-RAS colon cancer, which is resistant to drugs that inhibit the epidermal growth factor receptor (EGRF). They discovered that mutant K-RAS colon tumor organoids are very sensitive to a triple combination of an EGRF inhibitor, a MEK inhibitor, and an inhibitor of a molecule called BclXL. They hope to move this combination therapy into clinical testing.
- The Dream Team has determined that within individual tumors there can be significant differences (heterogeneity) and that this may mean that drug-resistant cells exist within a tumor even before treatment begins.