Chemotherapy for rare cancer fine-tuned with organoids

August 07, 2020

WINSTON-SALEM, NC - Aug. 10, 2020, - A patient-specific tumor organoid model is being used to identify the most effective chemotherapy protocol to treat appendix and colon tumors, a personalized medicine approach that is showing promise. The organoids were created by researchers at the Wake Forest Organoid Research Center (WFORCE), a joint effort by the Wake Forest Institute for Regenerative Medicine (WFIRM) and the Wake Forest Comprehensive Cancer Center.

Treatment for advanced stages of colon and appendiceal cancer with spread in the abdomen consists of cytoreductive surgery which removes tumors from the organs in the abdominal area which is then followed by hyperthermic intraperitoneal chemotherapy (HIPEC). As its name suggests, HIPEC is a cancer treatment that involves filling the abdominal cavity with chemotherapy drugs that have been heated at a specific temperature. Paired together, the two treatments increase life expectancy for patients that in the past were deemed candidates only for palliative approaches.

With the patient-specific tumor organoid model, doctors can test the effect of HIPEC on individual tumors to tailor the conditions needed for optimal effect, thus providing a personalized medicine approach for each patient. Appendix cancer is a rare disease and affects only 1 in 100,000 people while as many as 200,000 people in the U.S. are diagnosed each year with colon cancer.

"Patients undergoing the combination of cytoreductive surgery and HIPEC endure a long surgery that lasts for many hours," said Konstantinos Votanopoulos, MD, PhD, professor of surgery and Annals of Surgical Oncology.

The effect of intraperitoneal chemotherapy on the viability of the tumor of every individual patient is largely unknown, Votanopoulos said. "With this organoid platform we can quantify the impact of each drug in killing cancer cells. We can select the correct drug for the correct patient at the correct concentration and temperature, or even spare the patient from a procedure that will not substantially improve his or her outcomes."

An important finding of this work is that every tumor responds to heat differently with some tumors having showing dramatic response while others showing minimal or no meaningful response at all. The authors conclude this is probably related to genetically determined biologic machinery built in the cancer cells to counteract the impact of hyperthermia. Votanopoulos said a future hope would be to perform an image guided biopsy and grow organoids that will determine the optimal approach for each patient.

Shay Soker, PhD, a co-author and professor of regenerative medicine at WFIRM, said the study suggests that "the organoid model can accurately represent what occurs inside a patient's body. The research continues to show that organoids are promising candidates for drug screening to assist in clinical decision making as well as in the study of how environmental factors, viruses or toxins impact cellular function of both normal and tumor cells."

Organoids are tiny, 3D tissue-like structures created in the laboratory that mimic the function of human tissues and organs such as the heart, liver, lung, blood vessels, as well as cancerous tumors. The organoids are used as a testing and predicting platform to model diseases, evaluate efficacy and/or toxicity of new and existing drugs, and can also be used to test environmental hazards.

"Using a patient-specific tumor organoid model will eventually allow patients to be treated with the best available chemotherapy, while sparing the toxicity of drugs that are not effective for their specific tumor," said Steven Forsythe, MS, first author of the study.
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The study was supported by the Wake Forest Comprehensive Cancer Center Pilot Fund, the Wake Forest Dean's Hero Award, the Appendix Cancer Pseudomyoxoma Peritonei Foundation and the North American Organization of Rare Diseases.

Additional co-authors include Shyama Sasikumar and Hemamylammal SugavanamSivakumar of WFIRM, as well as Perry Shen, Edward Levine of Wake Forest, and Aleksander Skardal. Authors Soker, Skardal, SugavanamSivakumar, and Votanopoulos inventors on patent rights related to this work owned by Wake Forest University Health Sciences. The patents, whose value may be affected by publication, have the potential to generate royalty income in which the inventors would share.

About the Wake Forest Institute for Regenerative Medicine: The Wake Forest Institute for Regenerative Medicine is recognized as an international leader in translating scientific discovery into clinical therapies, with many world firsts, including the development and implantation of the first engineered organ in a patient. Over 400 people at the institute, the largest in the world, work on more than 40 different tissues and organs. A number of the basic principles of tissue engineering and regenerative medicine were first developed at the institute. WFIRM researchers have successfully engineered replacement tissues and organs in all four categories - flat structures, tubular tissues, hollow organs and solid organs - and 15 different applications of cell/tissue therapy technologies, such as skin, urethras, cartilage, bladders, muscle, kidney, and vaginal organs, have been successfully used in human patients. The institute, which is part of Wake Forest School of Medicine, is located in the Innovation Quarter in downtown Winston-Salem, NC, and is driven by the urgent needs of patients. The institute is making a global difference in regenerative medicine through collaborations with over 400 entities and institutions worldwide, through its government, academic and industry partnerships, its start-up entities, and through major initiatives in breakthrough technologies, such as tissue engineering, cell therapies, diagnostics, drug discovery, biomanufacturing, nanotechnology, gene editing and 3D printing.

Wake Forest Baptist Medical Center

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