273problematic as there is no ideal remedy for it. One compound, OC 144-093 (Ontogen
Corporation, Carlsbad, California) has passed phase I single blind, placebo-
controlled trials. This compound is orally active, non-toxic and does not interact
with paclitaxel.
P53 Mutations
The function of the human p53 gene, sometimes associated with drug-resistance,
remains only partially understood. In response to cellular stresses such as DNA
damage or oncogene activation, p53 acts as a tumor suppressor by blocking cell
division or inducing cell suicide through apoptosis. If p53 is mutated or otherwise
inactivated, a cell can accumulate further mutations that lead to tumor formation.
Furthermore, tumor cells with mutant p53 are typically unable to invoke apoptosis
in response to DNA damage, rendering such tumors resistant to traditional chemo-
therapy and radiation therapy.
Detection of Drug Resistance
Anaplastic Lymphoma Kinase
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase of the insulin
receptor superfamily. Translocations (fusions) of ALK have an established patho-
genic role in more than 250,000 new cancer diagnoses in the US each year. Detection
of ALK mutations has been considered increasingly important in the diagnosis and
therapy selection for many types of cancer, including NSCLC, diffuse large B-cell
lymphoma, anaplastic large cell lymphoma, neuroblastoma and infl ammatory myo-
fi broblastic tumors. Because of the potential for ALK-inhibitor therapies to treat so
many cancers, there are several ALK inhibitors currently in development by phar-
maceutical fi rms. ALK Assays (Insight Genetics) are based on the need for better
methods of not only detecting activating ALK fusions and upregulation across many
cancer types and but also monitoring for resistance mutations that arise in response
to ALK-inhibitor therapy. Insight ALK Screen assay provides quick, accurate detec-
tion of any ALK fusion. Insight ALK Resistance Monitoring assays assist in moni-
toring patients for ALK resistance mutations.
Metabolic Profi ling of Cancer
Acquired resistance to imatinib mesylate is an increasing and continued challenge
in the treatment of BCR-ABL tyrosine kinase positive leukemias as well as gastro-
intestinal stromal tumors. Stable isotope-based dynamic metabolic profi ling
(SIDMAP) studies conducted in parallel with the development and clinical testing
Therapy Resistance in Cancer