And yet, at the same time, an enormous amount of the clinical pipeline is cancer drugs these days.
There are almost 400 different compounds being tested in the clinic right now, just in the United States alone. That's a dazzling
array of trials to keep track of. It's very competitive these days.
One thing that's always puzzled me about cancer R&D is that, theoretically, one of the big victories would be drugs given
in early stages of disease. Yet the research is done in the most extreme cases, presumably because you can have much faster
clinical trials, and efficacy—measured by saving a couple of weeks of life—is often enough to get the compound past the first
hurdle. Is anybody working on drugs for early-stage cancer?
We do it this way basically because of an ethical concern. It would be a different story if we had good disease biomarkers—like,
say, increasing cholesterol levels for atherosclerosis in heart disease—but we don't.
And until those become available, if you're a cancer patient and your disease is detected early enough, surgery is the most
effective means of dealing with it. Unfortunately, that doesn't work for everybody. So then you're going to need chemotherapy.
And there is usually a set algorithm of choices of chemotherapeutics or radiation that have been shown to be effective in
one way or another. The treatment might be a little tough, but this is the standard of care. For a doctor to say to a patient,
"Let's not treat you with the standard of care, we want to use an experimental drug that may not even work"—well, that's a
pretty impossible argument. At most, they'll say to us, "Well, prove to me that it works in at least some setting and then
we'll think about it." That's why we start with the relapsed-refractory patients—first showing that the molecule is safe,
and then what it can do as a single agent against a specific cancer, and then in combinations with other therapies that look
like the standard of care.
Once you get approval, you're going to spend the next five to seven years doing additional clinical trials trying to move
your compound up toward first line. And if you're lucky enough and the compound is good enough, you'll finally reach standard
of care. That's one of the fundamental differences between an oncology drug and one for rheumatoid arthritis or asthma or
some other disease. This lack of biomarkers, coupled with the ethical considerations, is a very significant problem.
Let's get specific: Are there no biomarkers at all?
There are a very limited number. The classics are PSA for prostate cancer, CA-125 for ovarian cancer, and M protein for multiple
myeloma. There's really not a lot in breast cancer or colorectal cancer, for example, in terms of circulating markers, but
that's why mammograms and colonoscopies are useful.
In addition to finding biomarkers, what else can be done to improve the discovery and development of cancer drugs?
I'm more optimistic now than I ever have been, because we're starting to see this significant shift from old-fashioned cytotoxic
drugs. The vast majority of cancer treatments approved these days are targeted therapies generated over the past 10-plus years
with the input of molecular oncology, genomics, and all the other technologies that have been developed.
And we're going to figure out how to blend these targeted therapeutics in combinations so that we're treating the underlying
cause of the disease rather than its manifestations. Most traditional chemotherapeutics block proliferation, but targeted
therapies are aiming at the molecular elements of cancer. There are eight biological characteristics of cancer cells that
need to be addressed in order to attack these underlying disease mechanisms: self-sufficiency in growth signals, insensitivity
to antigrowth signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, tissue invasion, metastasis,
and therapeutic resistance.
These characteristics and their associated pathways are all being defined. And we are on the cusp of being able to use our
therapies more strategically because we can now profile a cancer at the molecular, rather than just the anatomical, level—and
that's where all the action is. The better we get at understanding the early aspects of disease, the earlier we'll be able
to target those pathways.