PDX Tumor Organoids: A New Tool in the Drug Testing Realm

A combination of two powerful technologies could be a huge win for preclinical cancer research and the 3Rs

The marriage of organoids and patient derived xenografts (PDX) to create 3D tumor models that are fully human are a hot area of drug discovery research. Recent data suggests this synergistic platform might finally be ready for prime time.

A pilot project conducted last year by Charles River Laboratories in partnership with the Institute of Clinical Pharmacology in Stuttgart developed PDX tumor organoids from four well-characterized breast cancer PDX and eight lung cancer PDX. They recently demonstrated that their PDX organoids can be used to screen single and combination therapies prior to analysis in PDX mouse models. While PDX organoids will not completely replace the efficacy studies done in mice, they do represent a reliable way of vetting and ultimately identifying the most promising oncology candidates for clients and then following up with smaller efficacy studies in mice if needed, which saves clients time, money and animals. 

The findings from these studies have opened the door to commercializing PDX organoids as a powerful, fully human model, says Julia Schueler, therapeutic area lead for oncology at Charles River. Schueler estimates the PDX organoid technology will reduce the need for mice in PDX studies by an astounding 50%.

Schueler said she will be sharing findings from the lung and breast cancer studies in two separate posters at the AACR meeting in April.  Her team is also in discussion with several clients to co-develop PDX organoids for their cancer product lines and is currently in the early stages of marketing this service to all of their PDX clients.

“I’m excited about where organoids will take cancer drug development,” said Schueler. “Being able to move to the next level and have a completely human model gives us the best chance at translatability. Having an animal-free 3D in vitro system like this could enable us to identify better candidates more quickly because at the end of the day, it’s all about the patients.”

A tool to improve drug selection

PDX models—what the industry has dubbed mouse avatars—have been stand-ins in the hunt for cancer cures for years, particularly for the robust immuno-oncology field. Organoid technology is a bit newer. The 3D in vitro tissue cultures, which mimic the structure and function of certain essential parts of an organ, are created by growing stem cells or tumor cells in a lab. Combining the two technologies is a way of improving the poor outcomes within drug development’s largest disease area. Currently, oncology drugs account for more than half of drugs in the pipeline, yet only 10 percent reach clinical trials or receive regulatory approval. This is in part due to the difficulties laboratories have in translating the animal data from their models into clinical practice. PDX organoids offer a workaround to this problem because they are fully human and therefore able to better capture which candidates to move forward.

The Charles River project looked at organoid panels of both cold and hot tumors—those unlikely to trigger a strong immune response vs. those whose behavioral patterns in vivo are well-understood—to increase the predictive strength of which population might benefit most from selected drugs. Since the patients who have hot or cold tumors vary, it is important to have models for both, says Schueler.

“Our ultimate goal was to be able to use organoids on client compounds instead of relying on a mouse, or afterwards doing a smaller study in the mouse,” says Schueler.

The validation process for PDX organoids

Yet Schueler said it was not easy developing the lung and breast cancer organoids. One of the major impediments holding back tumor-derived organoid technology, she says, has been that the science has applied to epithelial cells, while under-representing two critical components of the tumor microenvironment—human stromal cells and immune cells—that are important in finding successful candidate drugs, particularly in the immuno-oncology space.  Though not part of the immune system, stromal cells play a crucial role in supporting and regulating the immune response.

Last year, Charles River, as well as other labs, reached a major milestone by successfully co-culturing tumor organoids with immune cells, bringing the field closer to fully utilizing PDX organoids as a precision tool that could predict which populations of patients benefited from selected drugs. “We still need to solve the stromal cell problem, however,” says Schueler. “At the moment no one in the field has a solution for this, but we are all working on it.”

The market for PDX organoids

Though the number of companies developing PDX organoids is small, it is competitive, with a handful of companies vying for the biggest market share in this alternative technology space. Schueler says what sets Charles River apart from others is how well-characterized their PDX and organoid models are. “Clients are pleased to find that we have appropriate quality controls, which shows how robust our research is,” she said.

Along with organoids derived from PDX lung and breast cancer tissue, Schueler said her team is also eyeing the development of PDX organoids for pancreatic, renal, and ovarian cancer.

“We started with breast and lung cancer due to the medical need. Breast cancer is the most common in women worldwide and lung cancer the deadliest for both men and women. Between the two types of cancer there are more than 2700 drug candidates in development, which is why we started with those two types of PDX organoids first. We hope to soon expand our portfolio beyond that.”