Biology is Destiny
Chemotherapeutic agents prior to this point have all worked by inhibiting the metabolic pathways critical to cell division,
and none were specific to the cancer cells. Because of the inherent ability of cancer cells to mutate and build resistance
to this scattershot approach, a plateau has been reached in regard to clinical benefit.
Coming to the rescue is the increased understanding among researchers of cell biology, leading to the development of new lines
of attack against cancer, particularly tumors that carry multiple mutations and show resistance in individuals very quickly.
The emphasis today is on blocking mutated genes that fuel tumor growth, or on reprograming the DNA malfunctions that transform
a normal cell into a cancerous one. In that sense, biology has succeeded chemistry as the necessary prerequisite for further
progress against the disease.
The Right Drug for the Right Patient
Targeted therapies offer the potential to alter the molecular abnormality associated with the disease pathogenesis while reducing
the effect on normal cells. The first targeted therapy was tamoxifen for treatment of breast cancer. In the 1960s, the estrogen
receptor was described in breast tumors. Estrogen-blocking agents were studied in animal models in the early 1970s and tamoxifen,
a selective estrogen-receptor modulator (SERM), gained FDA approval in 1977. It was later found to be most effective in patients
whose tumors were considered to be estrogen-receptor or progesterone-receptor positive (ER/PR+). Tamoxifen has been shown
to reduce the risk of recurrence or contra-lateral disease as well as to decrease the annual death rate. It continues to be
widely used today.
The emphasis on targeted therapy has practical value beyond its scientific merits. Paired with a diagnostic assay, a targeted
drug can demonstrate efficacy in those patients most likely to benefit. This can result in more efficient use of resources
than the traditional shotgun approach of chemotherapy. Pairing the therapy with a diagnostic and then providing evidence that
the intervention works in the specific patient population is often a difficult and costly exercise which adds to the risk
of commercializing a promising compound.
Striking the Abnormal Chromosome
Therapies targeting constitutively active tyrosine kinases, or the specific chromosomal abnormality associated with a disease,
have become a recent focus of research. Tyrosine kinase activation results in downstream cell signaling and cell proliferation.
Various tyrosine kinases resulting from chromosomal abnormalities have been associated with the pathogenesis of many types
Chronic myelogenous leukemia (CML) was the first malignant disease found to be associated with a specific chromosomal abnormality.
What is known as the "Philadelphia chromosome" encodes for the protein mutation bcr-abl and leads to uncontrolled tyrosine
kinase activity. This chromosomal abnormality was first identified in 1961 when studying human leukemias and was then found
to be consistent in patients with chronic myelogenous leukemia.
It was not until three decades later that a specific drug able to target this protein mutation was recognized. Imatinib mesylate
(Gleevec) was identified from a library of small molecules which inhibit tyrosine kinases and found to decrease the number
of bcr-abl cells formed in patients with CML. After further studies identified efficacy in patients who had failed standard
treatment, the FDA granted accelerated approval of imatinib in patients whose CML had progressed after receiving interferon
alfa. Not long after that, trials were conducted in which imatinib demonstrated improved efficacy over standard treatment
as front-line therapy. As a result, imatinib has completely altered the course of CML, with long-term followup confirming
an eight-year overall survival rate of 85 percent, with relatively few adverse reactions.
Encouraged by the success of imatinib, other agents targeting specific tyrosine kinases are being actively investigated for
clinical use. The anaplastic lymphoma kinase (ALK) protein was first identified in anaplastic large cell lymphoma (ALCL) patients
and is now the subject of intensive efforts in other malignancies.
In 2007, a fusion of the ALK tyrosine kinase with the echinoderm microtubule protein (EML4) was identified in a subset of
non-small-cell lung cancer (NSCLC) patients. EML4-ALK occurs in approximately 2 percent to 7 percent of NSCLCs, most commonly
in younger patients who have never smoked. Unlike the inhibition of bcr-abl tyrosine kinases, which took decades to achieve,
crizotinib (sponsored by Pfizer; see "Planning Beyond the Petri Dish") was put into clinical studies within a few years of
the identification of EML4-ALK. A Phase I study of crizotinib in patients who had already failed at least one prior therapy
drug was recently published. Compared to traditional second-line therapy, which offers an average response rate of 10 percent,
patients receiving crizotinib had an overall response of 57 percent, with 33 percent of patients having stable disease at
a mean duration of 6.4 months. Crizotinib is now entering Phase III trials directly after Phase I comparing it to standard
therapy in patients who have previously been treated with a platinum agent and also as first-line therapy. These studies only
enroll patients with the specified mutation.
Despite these results, two secondary mutations conferring resistance to crizotinib have been described. This illustrates the
challenge of commercializing a target therapy when tumor resilience may lead to declining efficacy around the initial breakthrough.
From a public health perspective, the availability of follow-on therapies is critical to success in cancer treatment because
of cancer's capacity to use the body's own defenses to induce resistance to a drug.
Monoclonal Antibody Therapy
The rise of monoclonal antibody [MaB] drugs is testament to the dominant role that molecular biology now plays as the pathway
to new cancer treatments. These drugs work in various ways to either block the proliferation of growth receptors in cancerous
cells or to impede the blood supply that nourishes tumors. Monoclonal antibody drugs now account for a sizable share of the
oncology drugs market, with premium price points and sales that in a few cases exceed several billion dollars annually.
Bevacizumab (Avastin) is a humanized anti-VEGF (vascular endothelial growth factor A) monoclonal antibody. VEGF receptors
play a critical role in the development of angiogenesis—the formation of new blood vessels—by stimulating the recruitment
and proliferation of endothelial cells. By selectively binding VEGF—that is, inhibiting the binding of VEGF to its cell surface
receptor—bevacizumab decreases microvascular growth of tumor blood vessels and limits the blood supply to tumor tissues. Bevacizumab
currently has FDA-approved indications for use in four tumor types: colon, lung, kidney, and brain. Bevacizumab has also been
studied in metastatic breast cancer and found to significantly improve progression-free survival, while not affecting overall
survival. While improvements in progression-free survival initially were sufficient to gain FDA-accelerated approval for breast
cancer, this indication was withdrawn by the FDA late last year and is currently up for debate in an appeal filed by the drug's
sponsor, Roche. Further studies suggest there may be a subgroup of patients with tumors in which bevacizumab has greater impact.
Targeting: How Strong a Link?
As in all areas of research, better information allows for contradictions. Some—often unpublished—studies on targeted agents
show negative results. The challenge now is to determine which subset of patients will benefit from these therapies. Alternatively,
the goal is to determine who will not benefit, and therefore will be harmed by unnecessary toxicity and the avoidable costs of cancer therapy. Genotyping DNA from
tumor blocks of breast cancer patients in the bevacizumab study mentioned previously found that specific VEGF-genotypes predicted
a favorable median overall survival. Side effect issues are particularly important: the genetic variability of VEGF is also
a predictor of clinically significant hypertension. Grade 3 and 4 hypertension was associated with improved median overall
survival. Of course, these results still require validation, preferably in a prospective trial, as there are clear limitations
to interpretation of retrospective evaluations of biomarkers.