Cancer Drugs: Long Odds and Magic Bullets

By William C. Phelps, PhD


During 2011, the Food and Drug Administration (FDA) approved 30 completely new therapies (new molecular entities, as opposed to the modification of an old drug), 7 of which were for treatment of different types of cancer.  One of them, the lung cancer drug crizotinib, was decades in the making. For a new drug, that isn’t necessarily a lot of time.

Why does it take so long to get cancer treatments to the patients who need them? The answer lies both in the complexity of cancer and the complexity of the drug development and testing process. [more]


Seeking a ‘magic bullet’

A documentary film was released in 2006 called Penicillin: The Magic Bullet and it told the story of the remarkable discovery of what many consider medicine’s first great drug, which saved thousands of lives at the end of the Second World War. Penicillin was a magic bullet because it was extraordinarily safe and magically effective at killing bacteria that often caused lethal infections on the battlefield and beyond. 

It was within this context of hopeful expectations that cancer drug discovery got its start in the 1940s to find the magic bullet to kill cancer cells.

For several decades, the discoveries of cancer drugs resulted from a combination of educated guesswork, random testing, and luck.  During that time, we didn’t know a lot about the makeup and functioning of cancer cells.  Drug testing relied almost exclusively on a chemical’s ability to kill tumor cells just a little more effectively than normal cells.  As a result, many of the older cancer drugs carry substantial side effects for patients, leading to the impression that cancer treatment can be worse than the disease itself.   

Nevertheless, these traditional cancer drugs (e.g.  antifolates, antimetabolites, alkylating agents, antimitotics)  have been used for years  to cure testicular cancer as well as some forms of leukemia and lymphoma, and they are still in use today as part of carefully selected combination therapies for a wide range of cancers. In fact, these traditional or cytotoxic chemotherapies are what most people think of when they think about cancer treatment.


A more targeted approach

In the late 20th century, fueled by the “War on Cancer” and made possible by dramatic advances in molecular biology, researchers began to think differently about cancer drug discovery, leading to today’s focus on “targeted therapies.”  This approach focuses on a single gene or protein for which there is a good to fair understanding of how it works to cause cancer to develop or spread.  

A targeted cancer therapy is a drug which is designed to work directly on a single protein or enzyme, with the fewest possible side effects.  The expectation – and happily, the real experience for many — is that such targeted therapies are successful. They kill the cancer and they do so with fewer toxic side effects.  It is still early days in the development of targeted cancer therapies, so there is much that research and clinical experience has yet to teach us about this approach, but the results so far are very encouraging.


Long timelines and long odds 

Once a targeted therapy – or any other kind of drug — has been discovered, there is still a very lengthy process for getting it to patients.

The Tufts Center for the Study of Drug Development calculates that it requires, on average, 8 years of study from submission of an “investigational new drug application,” which permits initial testing in humans, to drug approval by FDA. These types of studies are called clinical trials.

In addition, more than 90% of drug candidates for human testing are likely to fail, due most commonly to lack of desired activity (it isn’t working as hoped) or unacceptable toxicity (people get too sick when they take the drug).  When compared to other types of drugs (e.g. for infectious diseases or heart disease), cancer drugs fail more often. This is due at least in part to the complexity of cancer itself. 


Not just one disease

As we learned in the past decade, the hundreds of diseases that we collectively call cancer are astonishingly complicated at the cell and molecular level.  While it is not terribly surprising that breast cancer cells are different from lung cancer cells, what is surprising is the huge differences seen among individual lung or breast cancers. For instance, there are at least 9 different types of breast cancer, some of which have additional sub-types themselves. Even individual patients with the same sub-type of cancer can look very different at a cellular and molecular level.

Personalized medicine is not a dream but increasingly a necessity as we understand that different tumor types such as lung, breast, and colon cancers must be defined according to their genetic profiles to help guide therapy for individual patients.  We also hope that such genetic definitions of cancer during clinical trials will improve the success rate of the drugs being tested, shortening the timelines and improving the odds of success.


Putting it all together

Crizotinib, which was approved for the treatment of some lung cancers, is a good example of how all these elements – understanding the complex nature of cancer, the rigors of drug development and testing – interact and eventually lead to a successful treatment.

Crizotinib targets an enzyme made by the Anaplastic Lymphoma Kinase gene (ALK). This gene was first discovered back in 1994 by scientists studying a rare form of non-Hodgkin lymphoma that affects both adults and children. As scientists learned more about ALK (more than 800 studies on it have been published since 1994), it became apparent that a drug targeting ALK might also be useful against neuroblastoma and a subset of non-small cell lung cancers, which have similar molecular defects. 

Only a small fraction of lung cancer patients have the ALK gene mutation targeted by crizotinib, but the drug is very exciting because it helps a type of cancer which is typically very hard to treat. And now that the drug is approved and on the market, it is being tested in other types of cancer with this ALK mutation.


Where we go from here

The pathway leading to FDA approval was made possible by a broad partnership between academic scientists, biopharmaceutical companies, the National Institutes of Health, and other nonprofit research-based organizations like the American Cancer Society.  No single entity could have done it alone. And it all took time. The first clinical trials of Crizotinib began in 2006, with FDA approval granted in 2011, nearly 2 decades after the original gene discovery in 1994, which itself built upon work first done in the 1980s! (For more information about why cancer research takes so long, see my previous blog about that subject.)

We are all impatient for drugs that can cure cancer no matter when and where we find it.  But the reality is we have to balance that wish with a desire for the safest and most effective drugs possible.  Fighting the war against cancer inevitably requires time, money, risk, and innovation to discover the magic bullets needed to save more lives.



Dr. Phelps is director of preclinical and translational cancer research for the American Cancer Society.

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