Cancer Cells Eat Themselves When Treated with Drug
Clinical trial to test safety of PI3K/AKT inhibitor
combined with sorafenib and regorafenib, which dramatically increased
Nov. 5, 2013 – It is too early for celebration but
the effective killing of colon, liver, lung, kidney, breast and brain
cancer cells with little damage to noncancerous cells in a preclinical
study at Virginia Commonwealth University Cancer Study has focused
attention on the new drug combination therapy that caused the cancer
cells to self-destruct.
The results are now the foundation for researchers
to plan a phase 1 clinical trial to test the safety of the therapy in a
small group of patients.
"It is still too premature to estimate when a
clinical trial will open to further test this drug combination therapy,
but we are now in the planning phase and encouraged by the results of
these laboratory experiments," says Andrew Poklepovic, M.D., oncologist
and member of the Developmental Therapeutics research program at VCU
Massey Cancer Center and assistant professor in the Division of
Hematology, Oncology and Palliative Care at VCU School of Medicine.
"We are also encouraged by the fact that the drugs
used in this therapy are either already approved by the FDA to treat
certain cancers or are currently being investigated in other clinical
Featured in the journal Molecular Pharmacology,
the study led by Paul Dent, Ph.D., demonstrated that the drugs sorafenib
and regorafenib synergize with a class of drugs known as PI3K/AKT
inhibitors to kill a variety of cancers.
Sorafenib and regorafenib work by blocking the
production of enzymes called kinases, which are vital to the growth and
survival of cancer cells. Sorafenib is currently approved by the FDA to
treat kidney and liver cancers, and regorafenib is currently approved
for the treatment of colorectal cancer. However, sorafenib and
regorafenib do not directly affect PI3K and AKT kinases, which are also
very active in promoting cancer cell survival.
The addition of a PI3K/AKT inhibitor to the
combination of sorafenib and regorafenib dramatically increased cell
death and was even effective against cells with certain mutations that
make one or the other drug less effective.
"We know that there are certain cellular processes
that are frequently dysregulated in cancers and important to cell
proliferation and survival, but if you shut down one, then cells can
often compensate by relying on another," says Dent, Universal
Corporation Distinguished Professor for Cancer Cell Signaling and member
of the Developmental Therapeutics research program at VCU Massey Cancer
Center as well as vice chair of the Department of Neurosurgery at VCU
School of Medicine.
"We are blocking several of these survival
pathways, and the cancer cells are literally digesting themselves in an
effort to stay alive."
Results of the study showed that the combination
therapy killed the cells by physically interacting with molecules to
block the survival pathways and induce a toxic effect known as autophagy.
Autophagy is a protective process where cells metabolize themselves when
starved of the resources needed to survive.
"Many groups are trying the approach of inhibiting
two survival signaling pathways, but our approach takes this further by
blocking significantly more of these pathways," says Dent. "Our findings
could benefit many different cancer patients based on the broad range of
effects seen in multiple cancer types."
In addition to Poklepovic, Dent collaborated on
this research with Steven Grant, M.D., Shirley Carter Olsson and Sture
Gordon Olsson Chair in Oncology Research, associate director for
translational research, co-leader of the Developmental Therapeutics
research program and member of the Cancer Cell Signaling research
program at VCU Massey; Laurence Booth, Ph.D., Instructor in the
Department of Neurosurgery at VCU School of Medicine; Gangadharan B.
Sajithlal, Hossein A. Hamed, Ph.D., and Nichola Cruickshanks, Ph.D., all
postdoctoral researchers in the Department of Neurosurgery at VCU School
of Medicine; and Jahangir Syed, M.D./Ph.D. student in the Department of
Biology at VCU.
This research was supported by National Cancer
Institute grants R01-CA141704 and R01-CA150214, National Institute of
Diabetes and Digestive and Kidney Diseases grant R01-DK52825, Department
of Defense grant W81XWH-10-1-0009 and, in part, by VCU Massey Cancer
Center's NIH-NCI Cancer Center Support Grant P30 CA016059.
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