Gordon B. Mills, MD, PhD, chairman, Department of Systems Biology, chief, Section of Molecular Therapeutics, Professor of Medicine and Immunology at the University of Texas MD Anderson Cancer Center, discusses examples of recent and unexpected responses to medications in diseases that did not have a treatment.

		Crizotinib (Xalkori), a recently FDA approved drug that targets the EML4-ALK translocation in non-small cell lung cancer, has shown remarkable responses including a disease control rate of 74% and a demonstrated 50% and 61% median objective response rate.

		Rapamycin analogs have demonstrated endometrial benefits in over 50% of patients.

		BRAF targeted therapies, such as Vemurafenib (Zelboraf), which is approved for BRAFV600E-positive unresectable or metastatic melanoma, have demonstrated remarkable progress, including a 74% reduction in disease progression.

In order to drive this type of therapy to the next level the first step will be to construct combinatory therapies. The field will begin to evolve from a short-term response that benefits a lot of patients, to a long-term durable response, and finally a cure.

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Dr. Gordon Mills from MD Anderson Cancer Center Gives Examples of Unexpected Therapy Responses

Dr. Mills Gives Examples of Unexpected Drug Responses

Gordon B. Mills, MD, PhD, chairman, Department of Systems Biology, chief, Section of Molecular Therapeutics, Professor of Medicine and Immunology at the University of Texas MD Anderson Cancer Center, explains that the field of targeted therapeutics was initially heralded as a "magic bullet" against cancer.

The ultimate paradigm at the onset of targeted therapy was the use of imatinib (Gleevec) for chronic myeloid leukemia (CML). This therapy incurred an incredible response in patients and the idea in place at the time was that this would be the standard for future targeted therapies.

Unfortunately this paradigm has not been realized in all cases of target therapies. Mills mentions that almost all other new agents are restricted to a subpopulation of patients and from those with the correct marker only a few will transiently respond.

This disappointment is the direct result of two mechanisms:

		Researchers failed to embrace that a clean and clear link showing a benefit to patients needs to be established between a combination of sensitivity and resistance markers and the drug to be used before you go to the clinic and needs to be modulated and modified within the clinic.

		It needs to be fully understood which resistance mechanisms are already in place or can be derived or evolved over time before the study moves to clinical trials in patients.

Dr. Gordon B. Mills from the University of Texas MD Anderson Cancer Center Discusses the Field of Targeted Therapeutics

Dr. Mills Discusses the Field of Targeted Therapeutics

Gordon B. Mills, MD, PhD, chairman, Department of Systems Biology, chief, Section of Molecular Therapeutics, Professor of Medicine and Immunology at the University of Texas MD Anderson Cancer Center, discusses utilizing systems biology for the development of new combination therapies.

Homeostasis in normal cells results in a rewiring of signaling pathways in order to maintain equilibrium. The homeostatic mechanism is not as strong in cancer cells but there is still a response that occurs when a targeted therapeutic is introduced.

Cancer cells enact a stress program in order to survive the stress of the therapeutic. This reaction can be exploited and used to create combinations that not only target the original tumor cells but also prevent resistance by targeting the compensation mechanism.

Mills explains that research is currently being focused on combinations that will be the most effective. The studies seek to establish a therapeutic index by examining systems biology for various combinations based on a comparison between the toxicity and efficacy of the treatment.

Dr. Gordon B. Mills from MD Anderson Cancer Center Discusses the Development of Combination Therapies

Dr. Mills on the Development of Combination Therapies

Gordon B. Mills, MD, PhD, chairman, Department of Systems Biology, chief, Section of Molecular Therapeutics, Professor of Medicine and Immunology at the University of Texas MD Anderson Cancer Center, explains how the make-up of a tumor cell makes it vulnerable to blocking signaling pathways.

Targeted therapeutics block important mediators of normal cell function. In a normal cell the homeostatic response mechanism allows it to withstand the stress of blocking the pathway but cancer cells lack this mechanism. A cancer cell is often reliant or addicted to a pathway and when it is taken away the cell lacks the ability to restore equilibrium and dies.

Mills explains that cancer cells have fewer back-up and survival mechanisms in place and this makes them far more vulnerable to blocking important signaling pathways. Cancer cells are far more vulnerable because they are far less robust than healthy cells.

Dr. Gordon Mills from MD Anderson Cancer Center Explains the Vulnerability of Cancer Cells

Dr. Mills Explains the Vulnerability of Cancer Cells

Gordon B. Mills, MD, PhD, chairman, Department of Systems Biology, chief, Section of Molecular Therapeutics, Professor of Medicine and Immunology at the University of Texas MD Anderson Cancer Center, explains that the management of cancer is shifting towards personalized care.

The goal of personalized medicine is to phase out the non-specific chemotherapy approach. Focusing on targeting the specific aberrations can reverse the adverse effects with better efficacy and less toxicity than non-specific chemotherapy.

Paradigms of personalized care already exist for breast cancer. A few examples include the HER2 marker for the use of Herceptin (trastuzumab) and the state of the estrogen receptor (ER) for the use of ER targeted therapies.

Establishing personalized medicine is not without a distinct set of challenges. There is a need to determine the aberrations that can be targeted, likely resistance mechanisms, and lastly how to prevent resistance from occurring.

Dr. Gordon B. Mills from MD Anderson Cancer Center Discusses Shifts Towards Personalized Medicine

Gordon B. Mills, MD, PhD

Articles

Dr. Mills Gives Examples of Unexpected Drug Responses

Dr. Mills Discusses the Field of Targeted Therapeutics

Dr. Mills on the Development of Combination Therapies

Dr. Mills Explains the Vulnerability of Cancer Cells

Dr. Mills on the Shifts Towards Personalized Medicine