Clinical trials for cancer, 1 patient at a time (EurekAlert, 15 July 2013)

Columbia University Medical Center (CUMC) researchers are developing a new approach to cancer clinical trials, in which therapies are designed and tested one patient at a time. The patient's tumour is "reverse engineered" to determine its unique genetic characteristics and to identify existing drugs that may target them.

The method analyzes the regulatory logic of the cell to identify genes and gene pairs that are critical for the survival of the tumour but are not critical for normal cells. FDA-approved drugs that inhibit these genes are then tested in a mouse model of the patient's tumour and, if successful, considered as potential therapeutic agents for the patient — a journey from bedside to bench and back again that takes about six to nine months.

It is known that tumours have a tremendous degree of heterogeneity within a patient and across different patients. When we expect different patients with the same tumour subtype or different cells within the same tumour to respond the same way to a treatment, we make a huge simplification. The idea behind this approach is to understand how tumours are regulated one at a time and then eventually the aim will be to treat patients individually.

Dr. Califano and his colleagues are currently testing this individualized approach to cancer in a handful of patients with gastric and neuroendocrine tumours. Based on what they have learned from these "N-of-1" studies, they are designing a new clinical trial protocol to study an estimated 30–40 patient with pancreatic, gastric, neuroendocrine, and other tumours that have not responded to conventional therapy. (In clinical trials, "N" refers to the number of patients in a study.)

The N-of-1 approach upends the traditional model of clinical trials, in which a compound is tested in a group of patients with a similar condition. If a high percentage of patients with a specific profile respond positively, researchers can predict that a similar percentage will do so in the future. Yet why some patients in a study respond while others do not is poorly understood.

Once the mechanism of the patient's individual tumour has been identified, the next step is to test a small number of the appropriate approved drugs, first in laboratory cultures and then in a "mouse avatar" —either an existing mouse model that closely matches the patient's tumour or one created by implanting the patient's tumour tissue into a mouse—so the drugs can be tested in vivo. Drugs that are effective in the mouse model, individually or in combination, would then be considered as a therapeutic option for the patient.

When a drug is effective, the researchers expect that other patients whose tumours have the same master regulators could be treated with the same drug, extending the benefits from one patient to many. And by targeting pathways unique to the cancer cells, the researchers hope to reduce undesired toxicity effects.

Source: EurekAlert (press release)