58° Congresso Nazionale SCIVAC: Oncologia veterinaria

58° Congresso Nazionale SCIVAC • Milano, 7-9 Marzo 2008 • Oncologia veterinaria - Alle soglie del III Millennio
A greater understanding of the pathogenesis and biology of cancer coupled
with major advances in biotechnology has resulted in the identification of rationally
designed, target-based anticancer therapeutics, with new therapeutic opportunities
and high expectations for the future as well as developmental challenges.
Because these agents appear to principally target malignant cells, it is expected
that they will produce less toxicity at clinically effective doses than nonspecific
cytotoxic agents. The innate complexity of the networks and cross-talks
that contain elements targeted by these agents also decreases the probability that
any single therapeutic manipulation will result in robust clinical activity and success
when used alone, particularly in patients with solid malignancies that have
multiple relevant signaling aberrations. The predominant therapeutic manifestation
of new biological agents in preclinical studies is due to decreased tumor
growth rates and will likely be similar in the clinic; however, such manifestations
are not readily detectable and quantifiable using nonrandomized clinical evaluations.
A lot of drugs have been discovered as active agents in cancer: gefitinib,
erlotinib sunitinib, sorafenib and others. For the most part, these agents have modest
activity when used as single agents in patients with previously treated cancer.
A major disappointment has been the failure of these novel agents to improve
survival when added to standard chemotherapy, calling into question the validity
of the preclinical model systems. Understanding the reasons why so many
compounds that appeared promising in preclinical and early-phase clinical studies
did not fulfill that promise when taken to large-scale randomized trials is a
critical question. Several key issues will need to be addressed in the investigation
of other novel compounds still in early development, primarily concerning the
selection, interpretation, and reporting of preclinical studies and the design and
interpretation of Phase I/II studies. Industry has moved too precipitously to bring
novel compounds into Phase III clinical trials in a competitive push to be the first
with a new class of agents. This accelerated advance to Phase III clinical studies
without better understanding of who may benefit from a given novel agent has
had the support of regulatory authorities and academic researchers anxious to
find effective regimens. A more thorough comprehension of the multiple growth
signaling pathways and of the roles of cross-talk, redundancy, and up-regulation
of compensatory mechanisms is essential to making targeted therapies effective
for more than small, difficult-to-define subgroups of patients. More research
needs to be directed at understanding basic mechanisms of tumor growth and resistance.
The recent pattern of negative Phase III trials threatens the future of the
field, if companies and other investors in research decide to reallocate resources
to disease conditions with a higher likelihood of successful outcomes.
Address for correspondence:
Giuseppe Curigliano
Department of Medicine - New Drugs Development Unit, European Institute of Oncology
Via Ripamonti, 435 - Milano
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