Unlocking the Gene Code
With the completion of the Human Genome Project in 2003, new technologies to detect genomic alterations have become available.
Scientists have begun to explore the complex genomes of tumors. Genome databases have been developed to assist in cataloging
new discoveries. Next-generation sequencing has provided the ability to more efficiently compare tumor genomes to normal genomes
of the same patient. Technology continues to work toward improving current techniques to provide increased information regarding
tumor genomes at a decreased cost. Researchers are relying on genetic sequencing to determine which malignant pathways are
active, regardless of where a tumor is located in the body.
Colorectal cancer (CRC) provided the first example of using this technology. The pathogenesis of metastatic colorectal cancer
is characterized by sequential accumulation of both genetic and epigenetic (does not affect underlying DNA sequence) alterations.
Ongoing research is focused toward translating the information regarding genomics research into clinically applicable predictive
or prognostic tests.
Previous biomarkers that were developed to predict the efficacy of anti-epidermal growth factor receptor (EGFR) antibodies
in patients with CRC exemplify the pitfalls of making assumptions about drug-target biology. Initial FDA approval of cetuximab
for treatment of CRC included a requirement that there be positive immunohistochemical staining for the presence of EGFR in
the tumor. It seemed reasonable that expression, and even perhaps the gene copy number, of the target would be required for
efficacy, but this does not appear to be the case. EGFR expression itself does not predict response to EGFR monoclonal antibody
therapy. EGFR-negative tumors have the potential to respond to cetuximab and thus EGFR immunohistochemistry before therapy
is not warranted.
The Kras oncogene, which is detected in 40 percent to 45 percent of cases of CRC, is a key molecule in the effects of EGFR
targeted therapy, as it is involved in an important downstream signaling cascade of EGFR. Activation of the Kras gene leads
to a constitutive activity of the protein, resulting in continuous cell proliferation and other activities that promote carcinogenesis.
When the Kras gene is mutated, degradation of the protein does not occur and activated Kras accumulates. This disturbed balance
of Kras activation and degradation leads to resistance to EGFR blockage. The mutation status of Kras has been found to serve
as a predictive factor for response to anti-EGFR-targeted therapy, such as cetuximab or panitumumab.
Thus, the research shows that administering EGFR-targeting monoclonal antibodies to unselected metastatic CRC patients can
no longer be considered the standard of care, as those agents will be ineffective in patients with activating mutations in
Kras. The test to determine mutational status is not yet confirmed. Despite the fact that mutations are binary events with
less room for interpretation than protein or mRNA expression-based tests, a balance between accuracy and practicality is still
needed. A number of options for mutation status testing are available, with all methods based on polymerase chain reaction
(PCR) testing platforms. Concerns include the difficulty of obtaining tumor samples suitable for molecular analyses (for example,
a concentration of mutant copies high enough to detect). In addition, the genetic heterogeneity of CRC means that the absence
of detectable Kras mutations in the primary tumor cannot formally exclude the presence of a Kras mutation in metastases.
Nevertheless, panitumumab for the treatment of patients with uncontrolled, or "wild-type," Kras tumors is the first example
of the approval of a drug therapy for solid tumors that is based on a genetic test. It opens a new era in biomarker-driven
therapy in this disease.
Combination Targeted Therapy
The combination of cytotoxic chemotherapy allows further cancer destruction and decreases tumor resistance. Hence it could
be a valid strategy in targeted molecular biologic therapies as well. But the results from trials appear inconclusive. In
one study, the combined effect of the MaB drug cetuximab and the current standard of care in metastatic colorectal cancer,
bevacizumab plus flouropyrimidine-based chemotherapy, resulted in a rate of progression-free survival that was significantly
shorter in the combined antibody therapy arm. The conclusion was that combining multiple forms of targeted therapies, specifically
anti-EGFR and anti-VEGF, may not be analogous to combining different types of chemotherapy, due to subtle interactions in
If combination monoclonal antibody therapy is not yet tagged as the next magic bullet, most drug companies are making it the
cornerstone of their research programs in cancer, accounting for the majority of the more than 800 anti-cancer compounds that
Pharmaceutical Research and Manufacturers of America (PhRMA) members have under development. Progress continues: A recent
study by The Ohio State University is optimistic about the combination of a targeted PI3K inhibitor with an agent that reverses
the epigenetic changes that cause gene silencing.
All this science is intuitive. Cancer development may involve either or both of these pathways—abnormal genes (or "oncogenes")
that regulate cell growth become activated and/or the genes that prevent cancer development (or "tumor-suppressor genes")
are silenced or turned off. More than 20 PI3K-targeted inhibitors have recently been introduced in clinical trials. More striking,
though, is that perhaps success of these agents is only achieved when administered in combination with epigenetic drugs for
synergistic effects. The recent study at Ohio State demonstrated activation of PI3K/AKT does play a role in epigenetic silencing
and lays the foundation for future therapies targeting both of these mechanisms.
Another new innovation unleashed by mapping the genome is the role that damage to DNA plays in destroying healthy cells. Poly
(ADP-ribose) polymerase, or PARP, is an enzyme which repairs damage done to our DNA by radiation or cell mutations. PARP-1
inhibitors are in a new class that causes inhibition of PARP function. BSI 201 and olaparib were the first of many now being
studied. Initial clinical trials showed efficacy in breast, ovarian, and prostate cancer. BSI-201 has shown efficacy in triple-negative
breast cancer, a type of cancer that unfortunately does not have many therapeutic options. These drugs represent a new investigational
option to treat BRCA gene-mutated cancers.
PARP inhibitor drugs show promise for two reasons: they demonstrate significant anti-tumor effects in several types of cancer
and have less side effects. Of note, these agents may also be effective in non-BRCA-mutated tumors. These agents are now in
investigation for a wide range of malignancies, including uterine and brain tumors, lymphomas, and chronic leukemias.