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Poet Richard Fox gains insight – and material – through cancer treatment
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Choosing mastectomy or not: Studying young women's surgical choices
Jeff's targeted therapy has kept his advanced lung cancer at bay.
Dana-Farber's interactive approach is exemplified by work on the
PI3 kinase (PI3K) pathway, from the discovery of PI3K in the
laboratory to clinical trials testing PI3K inhibitors in patients
with cancer. Key nodes of the PI3 kinase intracellular signaling
pathway are frequently mutated in cancer, particularly in solid
tumors of the colon, breast, lung, and brain, as well as sarcomas.
Since the 1980s when Thomas Roberts, PhD, co-chair of the Department of Cancer
Biology, co-discovered PI3K, scientists have been hunting for a
component of the kinase that could be targeted precisely - like
Achilles' heel - to shut down unrestrained cell growth of
Roberts and Jean Zhao, PhD, also of the Department of Cancer Biology,
subsequently found such a target: a catalytic subunit of PI3K,
termed p110α, which is encoded by the PIK3CA gene. In
their landmark study, Roberts and Zhao knocked out PIK3CA
in mouse cells and discovered that the cells remained stubbornly
resistant to oncogenic transformation, providing strong in vitro
evidence that p110αa might represent a selective therapeutic
target. They went on to show that formation of tumors arising from
inactivation of the tumor suppressor PTEN was blocked by the
knock-out of the PIK3CB gene encoding p110β, marking that
protein as a potential drug target as well.
Expanding on this work, Kwok-Kin Wong, MD, PhD, of Medical Oncology at Dana-Farber, and
colleagues from Massachusetts General Hospital investigated the
role of PIK3CA mutations in vivo. Wong genetically
engineered mice to express in lung epithelia the p110&alhpa;
activating mutation known as H1047R and then demonstrated that this
mutation is indeed causal. When Wong then treated the mice with a
PI3K inhibitor developed by Novartis, the tumors regressed
dramatically. Independently, Zhao obtained similar data for breast
tumors driven by the oncogenic PIK3CA in vivo.
Dana-Farber now has four different PI3K-inhibiting drugs (two
from Novartis, one each from Genentech and Exelixis) in clinical
trials, with more on the way, says George Demetri, MD, whose laboratory colleagues in the Sarcoma Disease Center have
demonstrated that PI3K pathway blockade is a promising therapeutic
strategy for gastrointestinal stromal tumors that become resistant
to matinib (Gleevec) and sunitinib (Sutent). "Dana-Farber is one of
the few places in the world with this number of PI3K inhibitors in
actual patient trials," remarks Demetri. "It reflects the
commitment we've made to translational research, as well as the
medical and scientific power we bring to collaborations with
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