2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

PI3 KINASE IN CANCER
Fig. 3. In vivo oral antitumor activity
and associated pharmacokinetic and pharmacodynamic
properties of GDC-0941 in
the PTEN null U87MG human glioblastoma
xenograft model. a) Chemical structure of
GDC-0941. b&c)Relative mean tumor volume
(percentage of initial volume before
therapy) and mean final tumor weights following
doses of 25, 50, 100, and 150
mg/kg daily oral doses of GDC-0941 administered
for 19 days. Tumors were
grown subcutaneously bilaterally in female
NCr athymic mice, and controls received
equivalent volumes of drug vehicle.
d) Tumors from the same efficacy study
were taken 4 and 8 hours following the
final dose. AKT SER473 phosphorylation and
total AKT were measured by a quantitative
electrochemiluminescent immunoassay.
For therapy data, results are mean
standard error (SE) of 16 mice. For pharmacodynamic
target engagement biomarker
data, results are mean SE of 6 mice.
Adapted with permission from Raynaud
and colleagues 2009. 17
not strongly proapoptotic but rather induce a strong and
durable effect on cell-cycle progression. 15,24 More profound
therapeutic activity is likely to require combinatorial treatments
to facilitate the death of cancer cells. Many combination
studies are underway, but because of the sheer number
of potential combinations, it will certainly take some considerable
time to identify optimal combinations; both preclinical
and clinical studies will contribute to this. Certain
rationally based combinations, for example, using PI3 kinase
together with MEK inhibitors that block the important
RAS-RAF-MEK MAP kinase pathway, have obvious mechanistic
rationale and these are being given a high priority in
clinical studies. 25 Both “horizontal” pathway targeting and
also “vertical” targeting within the PI3 kinase pathway are
being investigated. Another interesting opportunity is the
combination of PI3 kinase inhibitors with agents targeted to
the androgen receptor in prostate cancer. 29 In addition to
combinations with other molecularly targeted agents, use of
PI3 kinase inhibitors together with cytotoxic agents is also
being pursued.
The picture that we currently see emerging from the clinic
is that PI3 kinase inhibitors are generally well-tolerated
agents and show promising signs of biologic and clinical
activity. Concerns about potential effects on glucose metab-
Authors’ Disclosures of Potential Conflicts of Interest
Author
Employment or
Leadership
Positions
Consultant or
Advisory Role
Paul Workman Chroma
Therapeutics;
Nextech Invest;
Piramed (Roche);
Wilex
olism appear to have been alleviated, with only mild and
manageable changes being seen, at least with the doses and
schedules used to date. 27 The main side effects commonly
include skin rash and urticaria. Encouragingly, there is
early evidence of single agent therapeutic activity in the
current clinical trials in patients with cancer, 30 although
stable disease is often seen and it may require combination
studies to reveal the full therapeutic potential.
Concluding Remarks
The genetic validation provided by the frequency of PI3
kinase pathway deregulation in human cancers and evidence
from mouse models encourages continued efforts to
pursue inhibitors of PI3 kinases. The dramatic increase in
the number of PI3 kinase inhibitors that display fascinatingly
distinct selectivity profiles now provides us with many
powerful tools with which to further investigate disease
mechanisms and assess therapeutic potential in different
pathogenetic contexts. Continued efforts to define clinically
useful predictive biomarkers for patient stratification, together
with rational drug combination studies, will allow us
to uncover the full clinical potential of PI3 kinase inhibitors
in cancer treatment.
Stock
Ownership Honoraria
Research
Funding
Piramed (Roche) Piramed (Roche);
Yamanouchi
Expert
Testimony
Other
Remuneration
Paul Clarke Piramed Pharma Institute of
Cancer
Research
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