Oncology researchers have cultured tumor cell lines on plastic for decades, but these two-dimensional systems do not represent the complex tumorigenic process. An alternate approach uses patient-derived tumors implanted into mice to create more clinically relevant models of human cancer.
Molecular Response Laboratories maintains a bank of more than 144,000 living tumor specimens used to generate large populations of these mice—each harboring unique human tumors within. The company uses these surrogate patients—also know as patient-derived xenograft (PDX) mouse models—to directly evaluate drug candidates in preclinical studies for its clients.
This approach helps drug companies develop higher value therapeutics by figuring out which cancer types respond best to their drug and developing a molecular diagnostic approach before entering clinical trials.
In collaboration with its clients, Molecular Response has used its tumor collection to establish populations of PDX models not otherwise available. The company has a set of established PDX models available off the shelf to its customers, but very often will work with clients to establish custom models; the custom process usually starts by screening hundreds or thousands of tumors from the collection for a particular mutation or molecular characteristic, and then building those specific tumors into PDX models for in vivo pharmacology studies.
“It’s not enough to just have a PDX model with unknown genomic status. We use next-gen sequencing to characterize our PDX models, and we make that mutational information available to our clients so they can pick the right model for the study,” says Thomas Broudy, Ph.D., CSO. “That, in combination with the custom PDX builds we do, really creates a fantastic set of tools to help predict which patients are likely to respond to an investigational agent.”
Spectrum of Tumors
The company started in 2010 with the mission to improve personalized medicine by developing targeted oncology therapies. “We knew from the start that we needed to acquire tumor banks,” says Dr. Broudy. At about the same time, a 20-year-old clinical reference laboratory, which collected and stored patient tumor samples sent by physicians for drug testing, was closing down.
“That tumor bank was extraordinarily unique on two counts. First, the tumors stored were still living, which is almost unheard of, and something that is required if you want to test for a drug response. Second, it was the largest collection of its kind in the world. We acquired it and started using the tumors for preclinical pharmacology and diagnostic studies,” says Dr. Broudy.
The collection contains 144,000 living tumor specimens collected from 77,000 patients through biopsies and surgical resections. The collection covers 25 tissue types and 76 clinical diagnoses, including all known common and rare cancer indications. Major cancer types, such as lung, breast, colon, and ovarian, have about 5,000–10,000 specimens each, whereas small-cell-lung, neuroendocrine, and other less common cancers are also present in the hundreds.
“Our collection provides a spectrum of patient-derived xenograft models for testing investigational drug candidates,” says Dr. Broudy. Molecular Response Laboratories continues to scout for new tumor types to add to the collection, working with local medical centers to obtain other prospective, predefined specimens.
Discovery and Development
Clients of Molecular Response Laboratories include pharmaceutical and biotechnology companies that need clinically relevant models to screen oncology compounds and make decisions about which ones to advance, and which patients should be included in their clinical trials.
Dr. Broudy says the tumor bank helps with many of the stages of drug discovery and development including target identfication, target confirmation, patient selection, lead optimization, candidate selection, combination agent selection, indication expansion, and the holy grail of personalized medicine—companion diagnostic inclusion/exclusion testing (which the company performs in its clinical CLIA/CAP laboratory).
Molecular testing platforms the company uses include whole-genome microarray profiling, qPCR, fluorescent in situ hybridization, flow cytometry, and immunohistochemistry.
The in-house clinical testing lab at Molecular Response develops molecular tests based on novel mutations to evaluate drug responses. Among the newest is a clinically validated BRAF test that detects the V600E mutation found in ~50% of melanoma patients and 15% of colorectal cancer patients. The PCR-based test shows good sensitivity and sample acceptance, according to Dr. Broudy.
“We’ll be able to tell more patients if their tumor harbors the mutation, and they can use that information with their doctor to make better therapeutic decisions,” he says. The FDA has approved drugs that target BRAF mutations, such as Roche’s recently released Zelforaf™ (vemurafenib) for treating melanoma patients with the BRAF V600E mutation.
“The big question is ‘what will be the next BRAF for the next vemurafenib?’” says Dr. Broudy. “That’s where high-quality, clinically relevant, patient-derived models come in.”
To further characterize the development of novel therapeutics, Molecular Response Laboratories identifies or verifies mechanisms of action, as well as pharmacodynamic and predictive molecular markers. The company performs these analyses using its PDX mouse models, as well as through an ex vivo platform that marries 3D cell culture with high-content imaging. The ex vivo platform is a complex culture system that provides tumor cells with a growth environment much more similar to the original in-human setting—a key aspect of translating preclinical findings into clinical reality, says Dr. Broudy.
Other companies team up with Molecular Response Laboratories to make better oncology screening tools, he adds. A recent collaboration with Transparent in Chiba, Japan, resulted in a 3D cell culture system based on Transparent’s 3D cell culture plate design and Molecular Response Laboratories’ bank of living tumor cells. Transparent markets the product under its Cell-able Oncology™ brand, which allows primary tumor cells to grow in 3D cultures that closely resemble in vivo like conditions.
Pharmaceutical and biotechnology companies that team up with Molecular Response Laboratories enter into a collaborative partnership. “We work alongside our partners to move their compounds along the clinical development pathway,” says Dr. Broudy.