Horizontal and Vertical Signal Pathway Inhibition

The importance of signal pathway inhibition in human tumor primary culture microspheroids.

Signal transduction pathways are important targets in cancer therapy. Small molecule inhibitors for the tyrosine kinase and serine threonine kinase pathways are already available for clinical therapy. Additionally, compounds targeting the PI3K, AKT and MEK pathways will be available in the coming years. To explore the interaction of these parallel survival pathways, we compared activity and combined these inhibitors in human tissues — the results were instructive.

Our findings include favorable interactions between EGFr tyrosine kinase inhibitors and compounds that block the PI3K pathways. The most active combinations were those that inhibited the cross-talk between pathways (horizontal inhibition) over drug combinations that targeted the same pathway at different downstream points (vertical inhibition). Similar observations have been made combining PI3k inhibitors and MEK inhibitors. One such report in PNAS (May 10, 2010) closely paralleled the work conducted in our laboratory, Rational Therapeutics, that we reported at the AACR.

Noteworthy, a series of studies utilizing these combinations, indicate that certain tumors respond to their drug exposure by undergoing autophagic death, not necrotic or apoptotic. This distinction is possible, as the Ex-Vivo Analysis of Programmed Cell Death (EVA-PCD®) platform has the capacity to measure all forms of cell death – apoptotic and non-apoptotic.

We continue these studies in numerous solid tumors to explore those diseases that will be the best candidates for these types of combination therapies. Please leave a comment below if you would like more information on these studies.

About Dr. Robert A. Nagourney
Dr. Nagourney received his undergraduate degree in chemistry from Boston University and his doctor of medicine at McGill University in Montreal, where he was a University Scholar. After a residency in internal medicine at the University of California, Irvine, he went on to complete fellowship training in medical oncology at Georgetown University, as well as in hematology at the Scripps Institute in La Jolla. During his fellowship at Georgetown University, Dr. Nagourney confronted aggressive malignancies for which the standard therapies remained mostly ineffective. No matter what he did, all of his patients died. While he found this “standard of care” to be unacceptable, it inspired him to return to the laboratory where he eventually developed “personalized cancer therapy.” In 1986, Dr. Nagourney, along with colleague Larry Weisenthal, MD, PhD, received a Phase I grant from a federally funded program and launched Oncotech, Inc. They began conducting experiments to prove that human tumors resistant to chemotherapeutics could be re-sensitized by pre-incubation with calcium channel blockers, glutathione depletors and protein kinase C inhibitors. The original research was a success. Oncotech grew with financial backing from investors who ultimately changed the direction of the company’s research. The changes proved untenable to Dr. Nagourney and in 1991, he left the company he co-founded. He then returned to the laboratory, and developed the Ex-vivo Analysis - Programmed Cell Death ® (EVA-PCD) test to identify the treatments that would induce programmed cell death, or “apoptosis.” He soon took a position as Director of Experimental Therapeutics at the Cancer Institute of Long Beach Memorial Medical Center. His primary research project during this time was chronic lymphocytic leukemia. He remained in this position until the basic research program funding was cut, at which time he founded Rational Therapeutics in 1995. It is here where the EVA-PCD test is used to identity the drug, combinations of drugs or targeted therapies that will kill a patient's tumor - thus providing patients with truly personalized cancer treatment plans. With the desire to change how cancer care is delivered, he became Medical Director of the Todd Cancer Institute at Long Beach Memorial in 2003. In 2008, he returned to Rational Therapeutics full time to rededicate his time and expertise to expand the research opportunities available through the laboratory. He is a frequently invited lecturer for numerous professional organizations and universities, and has served as a reviewer and on the editorial boards of several journals including Clinical Cancer Research, British Journal of Cancer, Gynecologic Oncology, Cancer Research and the Journal of Medicinal Food.

5 Responses to Horizontal and Vertical Signal Pathway Inhibition

  1. don lewis says:

    How do these signals effect isotropics? Or is it just fm horizontal

    • I am a little puzzled by the question. In physics and radtion, isotropics refers to “equality in all directions” with regard to forces and radiation. In this context I am a bit less clear. Is the question, “equally” effective drugs for the differing pathways? Perhaps I do not fully understand the inquiry.

  2. Amanda says:

    I’m very encouraged to read this post.

    Ability to evaluate the emerging targeted drugs in a lab; before being offered to patients will be very valuable to numerous patients like me who have failed standard therapies and bank on clincial trials where success rates are so minimal. You offer us a lot of hope.

    I’m a breast cancer patient and have been recommended some clinical trial – a combination of a PI3K Inhibitor and Docetaxel or another Dual inhibitor that targets two/three different pathways. I was wondering if you test such combinations of targeted drugs in your lab? And what has been the success rates (in terms of remissions; etc) when active drugs were administered to patients? I think this information will be very valuable to many patients who are selecting clinical trials rather than a random shot in the dark.

    I was also intrigued by your comment – “The most active combinations were those that inhibited the cross-talk between pathways (horizontal inhibition) . Similar observations have been made combining PI3k inhibitors and MEK inhibitors” Does this mean that a dual PI3K inhibitor and MEK inhibitor would be more effective than a PI3K and AKT Inhibitor? If you could direct me to any material that offers more information (either published or your own study); I would very much appreciate it.

  3. Amanda:

    Your inquiry is very sophisticated. Indeed we do test many of these compounds in the lab. Our most recent work has been focused upon a dual PI3K/mTOR inhibtor and a dual MEK/ERK inhibitor. In some tumors, one drug may be more active. In other tumors the combination proves best. This would suggest that some tumors are driven by one pathway while others have dual triggers, that both must be shut off to acheive cell kill.

    Our initial experience was with the EGFr inhibitors(Gefitinib and Erlotinib). Many years ago we found that they were active in NSCLC and that a subset of patients were very sensitive. Several years later these very sensitive patients proved be the EGFr mutated group. Of interest, the EGFr mutant group currently respond to these drugs about 70% when selected by mutational analysis. We have actually had a much higher response rate when we select based upon our functional platform (as we reported at ASCO in 2007). Unfortunatley, we do not have access to every one of the newest agents for clinical use and for that reason we do not have as large a correlative data base. We would welcome the opportunity to select candidates for these newer agents using our platform and will keep you apprised of our progress over time.

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