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San Antonio 1K Cancer Genomes Project Aims to Couple Clinical Outcomes with Genomic Alterations

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South Texas Accelerated Research Therapeutics, or START, and BGI Tech kicked off a project last week that aims to sequence at least 1,000 and potentially up to 10,000 cancer genomes from patients at primary diagnosis and correlate the genomic alterations with extensive clinical outcome data about the patients' drug regimen and disease progression.

The goal of the project is to aid cancer drug development by identifying both new targets as well as gaining a better understanding of response and resistance to existing drugs.

START will collect the patient specimens and clinical data, while BGI Tech, the commercial services subsidiary of BGI, will perform the sequencing.

START is based in San Antonio, Texas, but also has offices in Madrid and Shanghai, and it directs clinical trials of anticancer agents. Its mission is to accelerate drug development to improve outcomes and survival for cancer patients.

According to Anthony Tolcher, clinical director at START, there are several key facets that set this tumor sequencing project apart from other tumor sequencing projects, including the sheer amount of clinical data that will be available with the tumor samples, the fact that the samples will be collected mainly from community hospitals rather than cancer centers.

Additionally, one of START's main ongoing research programs is creating mouse tumor models from patients' tumors. Tolcher said that many of the volunteers participating in the sequencing project will also have tumor mouse models, which will enable the direct testing of compounds and help couple patients' genomic profiles with drug response.

Other large-scale sequencing projects such as The Cancer Genome Atlas, tend to have limited clinical data associated with the samples. "The problem with that," he said, is that the TCGA is "missing the ability to delve into and understand hierarchy — which genes are important and which genes are altered but have no value.". Without detailed clinical information, it becomes difficult to distinguish driver from passenger mutations.

Additionally, for many cancer sequencing studies specimens are being collected from the large academic cancer centers, which "tend to have the worst of the worst patients," he said. Using only these patient samples with the worst clinical outcomes "can cause us to pursue the wrong leads in clinical trials," he said. "We need to understand the run-of-the-mill type cancer."

As such, he said that the tissue samples for the San Antonio project are being collected from community hospitals, since that is where most patients receive a primary diagnosis.

Tolcher said the group is working with over 200 San Antonio-area oncologists, cancer surgeons, pathologists, and researchers from around 14 hospitals to collect fresh frozen, biopsied tissue samples.

Already, 1,200 patients have signed up, and while the initial goal is to sequence 1,000 cancer genomes, Tolcher said that ideally, he'd like to sequence 1,000 of each of 10 cancer types — breast, ovarian, endometrial, prostate, renal cell carcinoma, melanoma, lung, gastric, glioblastoma, and colon.

So far, the group has raised around $1.1 million and has a goal of raising $5 million. The nonprofit ThriveWell Cancer Foundation is responsible for collecting and managing the funding.

The first 100 cancer and matched normal tissues will be sent to BGI in the next few weeks for sequencing, Tolcher said, with initial results expected around six to eight weeks following. Sequencing will initially be done on Illumina's HiSeq instruments, although Tolcher said that could change throughout the course of the five-year project.

Patients have also consented to making de-identified data publicly available, and some are interested in receiving genomic information about their tumors to potentially help guide their own treatment regimens.

"We're doing what's called a subtraction technique, so just looking at what's gone wrong [to cause] the tumor," Tolcher said. The researchers will not return or make public incidental findings or information that could be used to identify the person.

"By doing that, you boil the numbers down to around 200 megabases of data, which can be given to a patient on a flash drive," he said. "So if people want the information, we'll provide it."

START has developed its own software, Clinical Synchrony, in order to integrate genomic data with treatment and survival data into electronic records.

Whether or not the information will ultimately help the volunteers that have enrolled in the study is a harder question to answer, Tolcher said.

The team also plans to create mouse models of individual patients' tumors, which will be used to test drugs. Already, 450 mouse models have been created from volunteers' tumors that will ultimately be sequenced.

"We want to marry genomics to clinical outcome, but also have actionable models to test drugs in and determine whether one particular genomic profile predicts that you'll respond to a particular class of agents," Tolcher said.

He thinks such a method could help speed up the drug development process. Currently, "the process of phase I and then phase II and figuring out which patients get benefit and which don't is slow and laborious," he said.

Instead, creating patient-derived explant models will hopefully enable the researchers to "early on figure out the genomics that predict for sensitivity for some of these targeted therapies," he added.

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