Bill Gates Thinks Cancer Therapies Could Serve a Much Wider Purpose


IN BRIEF

During a recent keynote address, Bill Gates advocated the creation of a bridge between the private sector and global health, nothing that research conducted by the former could help treat the problems of the latter.

A WIN-WIN SCENARIO

Bill Gates has high hopes for the future of cancer research, and not just in the battle for which it’s intended. The philanthropist thinks the same therapies researchers are developing to fight cancer could one day be used to “control all infectious diseases.”

Gates made the claim during his keynote address at J.P. Morgan’s Annual Healthcare Conference in San Francisco. He told the audience that the immunotherapy used to treat cancer patients in the world’s more prosperous nations could eventually be used to control infectious diseases such as HIV, TB, and malaria in its poorest.

Unfortunately, according to Gates, the pharmaceutical and biotech companies conducting this research may not see any incentive to pursue such applications, but they should.

“[I]n health — as in many other aspects of life — the free market tends to work well for people who can pay…and not so well for people who can’t,” said Gates. “But over the last decade, our experience has shown that we can stretch the reach of market forces so the private sector’s most exciting innovations also benefit people with the most urgent needs.”

Gates told the audience that the private sector can benefit from achieving breakthroughs in global health, noting that developing economies are growing much faster than developed ones. Additionally, he believes the Gates Foundation can help mitigate any risk to the private sector by providing “more predictability” and by investing in companies with the technologies that could be useful for global health.

BEYOND CANCER

In 2016, an estimated 445,000 people died from malaria, 1 million from HIV-related illness, and 1.7 million from TB (including 0.4 million with HIV). If cancer treatments could prevent the spread of these diseases and help treat those already infected, we could see a significant decline in these figures.

But cancer research is just the start. As Gates said in his keynote, research to treat other health problems of “rich-world markets” could help doctors address the problems of poorer ones.

For example, research into neurodegenerative diseases such as Alzheimer’s could be useful for those trying to treat the hundreds of millions of children with cognitive development issues due to growing up in poverty. Meanwhile, researchers in Africa and South Asia attempting to address undernutrition may glean valuable insights from obesity research.

By creating a bridge between the private health sector in developed nations and the global health community, we can ensure that all the world’s citizens have access to the best treatment options available. As Gates concluded in his keynote, reaching this goal of health equity in our lifetime isn’t just a possibility — it’s an imperative.

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To Eat or Not to Eat: With Cancer Therapies, That Is the Question.


When we are healthy, we tend to eat what we want, when we want, and without much thought about how our bodies process food and anything else we ingest. But what we eat and when we eat it can affect the way our bodies absorb and react to medications, sometimes to the extent of altering treatment outcomes.

Food intake, therefore, is an important variable when determining the optimal treatment for many diseases. And cancer researchers are now exploring whether manipulating food intake could help reduce the side effects of some treatments or make them more effective, as well as more cost-effective.

A Double Challenge to Cancer Cells

What we eat and when we eat it can affect the way the body absorbs and reacts to cancer treatments.

In 2008, the laboratory of Dr. Valter Longo, a professor of gerontology and biological science at the University of Southern California (USC), showed that fasting for 2 to 3 days protected normal cells and mice from chemotherapy drugs without protecting cancer cells—an effect they called differential stress resistance.

Dr. Longo and oncologists from USC later published a study of 10 elderly cancer patients who voluntarily underwent short-term fasting before and/or after cytotoxic chemotherapy infusion. Patients reported fewer side effects, including fatigue, weakness, and gastrointestinal problems, when they fasted. However, some doctors still worried that fasting could also protect cancer cells, explained Dr. Longo, which would negate its use in cancer patients.

A recent study by the USC research team, published March 7 in Science Translational Medicine, addressed this concern by showing that, contrary to such fears, fasting renders cancer cells more sensitive to chemotherapy.

The researchers found that fasting conditions in cell culture and in mice caused normal and cancer cells to radically change their gene expression patterns—but in very different ways. Normal cells reduced the expression of genes associated with cell growth and division and diverted their energy to cellular maintenance pathways that protect normal cells from stressful conditions and repair stress-induced damage. In contrast, cancer cells reduced the expression of many protective genes, which made them more likely to die, explained Dr. Longo.

Fasting results in “more investment in a variety of systems that protect the [normal] cell,” Dr. Longo said. This shift to maintenance (instead of growth) has an added benefit for normal cells: Nondividing cells that enter a maintenance mode are less likely to be damaged by chemotherapy drugs that target the process of cell division.

In contrast, cancer cells contain mutations that may hinder their ability to respond to starvation conditions by shifting their resources away from growth, as normal cells do. Fasting also deprives cancer cells of the glucose and other molecules they need to fuel their endless cell division. Therefore, fasting adds a second stressor on top of chemotherapy, forcing cancer cells to deal “with two extreme environments at once,” explained Dr. Longo.

Fasting adds a second stressor on top of chemotherapy, forcing cancer cells to deal with two extreme environments at once.

—Dr. Valter Longo

This combination of stressors led to promising results in animal studies. In mice with implanted breast cancer cells, short-term fasting alone delayed tumor growth to the same extent as treatment with the drug cyclophosphamide. Fasting before administering the drug had a stronger effect: the tumors of fasting mice given cyclophosphamide grew to less than half the size of those in nonfasting mice. The researchers saw similar results in mice implanted with melanoma or glioma cells.

In mouse models of metastatic melanoma, breast cancer, and neuroblastoma, fasting combined with high-dose chemotherapy extended survival compared with high-dose chemotherapy without fasting. The combination also reduced the overall number of metastatic tumors. Moreover, 20 to 40 percent of fasting mice with neuroblastoma had a long-term remission, which was not observed in mice that received chemotherapy without fasting.

The USC team is now studying how fasting can reduce side effects in people receiving chemotherapy. Dr. Longo has helped design three ongoing early-phase clinical trials examining this question (at USC, the Mayo Clinic, and Leiden University in the Netherlands).

And a consortium of 12 hospitals in the United States and Europe is planning two trials, each with more than 800 patients, Dr. Longo noted. One trial will look at whether fasting can reduce chemotherapy side effects, and the other will look at whether fasting can influence both side effects and drug efficacy (as observed in mice).

According to a survey by the USC team, more than 70 percent of eligible patients would refuse a water-only fast, so the international trials will use a substitution diet called Chemolieve that the research team developed and commercially marketed under an NCI Small Business Innovation Research (SBIR) contract. The researchers designed the diet to provide a minimum amount of nutrients to cancer cells while providing nourishment to the patients, sparing them the discomfort of fasting.

Danger, But Also Opportunity

On the flip side of the coin, researchers at the University of Chicago are exploring whether the bioavailability of some oral cancer drugs—the amount of drug absorbed and used by the body—can be increased by taking the drugs with food.

For many oral drugs, whether a patient takes them with food is irrelevant. But some oral drugs have a clinically significant food effect, which means that taking them at the prescribed dose with food causes a substantial change in their bioavailability. If a food effect leads to a marked decrease in bioavailability, too little drug will reach the bloodstream. If a food effect leads to a large increase in bioavailability, patients taking the drug with food risk overdosing.

This second scenario is a concern for several oral cancer drugs, including nilotinib (Tasigna) for chronic myelogenous leukemia and lapatinib for advanced breast cancer. The risk of sudden cardiac death from taking nilotinib at its prescribed dose with food is so high that the manufacturer has included a boxed warning about the dangers and developed a corresponding risk evaluation and mitigation strategy.

Dr. Mark Ratain, professor of medicine at the University of Chicago, sees opportunity instead of danger in the food effect, as well as a major flaw in what has become the default strategy for oral cancer drug development.

Oral Cancer Drugs That Are More Potent When Taken with Food

Cancer Drug

Approximate Increase in AUC*
When Taken with Food

Estimated Monthly Cost at the
Prescribed Dose (2011)

Lapatinib

150%

$3,400

Nilotinib

100%

$8,800

Erlotinib

 50%

$4,800

Pazopanib

100%

$6,000

Abiraterone

300%

$5,000

*AUC = area under the curve; a measurement used to estimate the bioavailability of drugs. (Data courtesy of Dr. Mark Ratain, University of Chicago)

For many noncancer drugs that have a greater bioavailability with food, that food effect has been exploited, explained Dr. Ratain. For example, drugs such as darunavir for HIV or telaprevir for hepatitis C are prescribed at lower doses to be taken with a meal.

In oncology, the opposite has happened. Discovery of a food effect has led to the development of a high prescribed dose to be given without food. “That’s not convenient for patients” who may take these drugs for years and are otherwise healthy, said Dr. Ratain, such as patients with chronic myelogenous leukemia who achieve complete remission on nilotinib but who must continue taking the drug every day.

Testing oral oncology drugs that have a food effect at lower doses with food might substantially reduce side effects and costs, suggests Dr. Ratain. His research group is testing this concept in a phase II clinical trial of abiraterone acetate (Zytiga), approved for metastatic prostate cancer. Dr. Ratain and his colleagues are testing whether men can safely reduce their dose of the drug by 75 percent by taking it with food. And, in turn, reducing the dose might cut drug costs, he added.

Some oral drugs have what scientists call a clinically significant food effect—taking them at the prescribed dose with food causes either a major increase or decrease in bioavailability.

The researchers are randomly assigning participants to one of two treatment groups: the approved dose of 1,000 mg without food or 250 mg taken with a low-fat breakfast. The reduction in prostate-specific antigen (PSA), variability in pharmacokinetics, and effects on the hormonal targets of the drug will be compared between the two groups.

“When one is starting with a drug and wants to study the pharmacokinetics in healthy volunteers, the cleanest thing to do is to study [the drug during] fasting. But just because fasting potentially provides less variability in dose between patients, that doesn’t mean it’s the best way to administer any given drug,” said Dr. Ratain. “We’re asking questions that I think the FDA should require companies [to answer]—what is the variability [in dose] over time, with food and with fasting?”

This is beginning to happen. The FDA’s Center for Drug Evaluation and Research (CDER) now recommends to all pharmaceutical sponsors that “the impact of food intake on oral oncology drugs should be assessed early in drug development—during the pre-Investigational New Drug (IND) and phase I development periods,” said Dr. Atiqur Rahman of CDER’s Office of Clinical Pharmacology.

“Information obtained from these evaluations should be incorporated in the phase II and phase III development trials to guide dosing recommendations with regard to food intake,” he continued. CDER also informs the sponsors that studying food effect in the late phase of drug development may be necessary if the formulation or dosage is significantly altered from the one tested during early clinical development.

But “whether a particular oral oncology drug can be allowed to be developed with food will depend on many factors, such as the magnitude and variability of the food effect, the therapeutic window of the drug, as well as the characteristics of the disease and the patient population,” Dr. Rahman concluded.

Source: NCI.