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New approach to treat Chronic Lymphocytic Leukemia

Our team is working on a promising new approach to treat Chronic Lymphocytic Leukemia (CLL).  Early results indicate that FDA-approved drugs commonly used to treat CLL can be dramatically more effective when combined with temporary fasting or “fasting mimicking diets” (FMD).

Preliminary in vitro (test-tube) studies by our research team have already demonstrated 100% kill rate of CLL cells using a combination of specific FDA-approved agents and FMD. Additionally, fasting appears to protect normal cells from the side-effects (toxicity) of these agents. We are seeking funding for the next stage of this research so that we can test the same combinations of FDA-approved agents in mouse models, prior to moving to human studies. A major advantage of the research is that beneficial outcomes could become rapidly available to CLL patients, since the treatment approach is based on dietary therapy plus FDA-approved drugs.

What are we proposing to do?

Our initial in vitro research using mouse CLL cells found that a combination of three common cancer drugs, which when given with dietary restriction, succeeded in killing 100% of the CLL cells.  This is a very promising result.

This initial set of experiments on CLL was funded by a donation from a private individual.  This donor has already agreed to fund one-third of the next $300,000 of budgeted costs, but the team needs to raise an additional $200,000.

The aim of this current study will be to:

  1. Test the efficacy of various combinations of cancer drugs in conjunction with the FMD in the treatment of multiple mouse CLL cancer models. We will also determine the effects of this therapeutic intervention on the survival of tumor-bearing mice.
  2. Test the toxicity of various combinations of cancer drugs in conjunction with the FMD on various normal cell types and organs/systems.

These studies are required before a human clinical trial can commence.

Why is this important?

The American Cancer Society’s estimates about 14,620 new cases of CLL and about 4,650 deaths from CLL in the United States alone for 2015.

The incidence of this leukemia is high in both men and women and although most patients live for many years with the disease, it can rarely be cured.  CLL treatment is often administered intermittently, and may also increase the risk of developing a second malignancy as skin and lung cancers, or other types of leukemia, lymphoma, and other cancers. Living with the threat of CLL progression can be difficult and very stressful.

Who will benefit from the results of this project?

Most new anti-cancer drugs cost up to a billion dollars of investment and take around 10-15 years before they hit the market. In contrast, since this new treatment approach is based on a dietary therapy already undergoing clinical testing for other cancers plus standard drugs already approved by the FDA, it could become widely available, quickly.

In summary, a positive outcome to this study could lead to the rapid deployment of an effective, low toxicity, and low cost treatment for CLL, leading to improvements in the overall survival and the quality of life of thousands of people currently living with leukemic cancers.

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About our Team

Our team is led by professor Valter Longo of the University of Southern California Leonard Davis School of Gerontology in Los Angeles, USA and of the IFOM, Molecular Oncology Institute in Milan Italy.  Over the past ten years, the Longo lab demonstrated that periodic cycles of short-term fasting protect mice and possibly humans from the toxic side effects of chemotherapy, while increasing the chemotherapy’s toxicity to a wide variety of malignant cells including breast cancer, melanoma, neuroblastoma, colorectal cancer and CLL.

The Longo laboratory has developed a “fasting mimicking diet” (FMD) that produces the same effect as fasting while allowing the subjects to eat some food. This new diet is currently being tested in combination with chemotherapy in at least 9 clinical trials ongoing at Norris Cancer Center (3 trials), Mayo clinic (1 trial), Leiden University (2 trials), Charite University (2 trials), University of Genoa (1 trial) based on our previous research at USC. To date, a total of 43 breast cancer patients have been enrolled and preliminary analysis of self-reported side-effects, suggests improvements.

More scientific details about this project:

CLL, the most common form of adult leukemia (or blood cancer) in the United States and European countries, results from the progressive clonal expansion of leukemic cells derived from normal lymphocytes.

There are no standard therapies for CLL and the existing treatment options (combinations of chemotherapy and immunotherapy) can cause severe, even life-threatening side effects. Even the most effective treatments do not work on everybody and drug resistance is common.

The following is some basic human cell biology that explains the foundation of the work proposed here. When there is a normal nutrient supply, most human cells replicate by cell division and this requires DNA and protein synthesis and high metabolic rates in order for the new daughter cells to have all the necessary components to be formed and function. When there is a restricted nutrient supply, these normal cells focus on survival rather than on cell replication, minimize DNA and protein synthesis and enter a highly protected state.

In contrast, cancer cells are stuck in a “reproduction mode” and undergo fast cell division and replication which require rapid DNA and protein synthesis.  They are also much worse than normal cells in adapting to novel environments such as the complex one formed by combining extreme dietary conditions and cancer drugs. As a result, they become stressed and die. Our laboratory has previously shown that a diet that mimics fasting (FMD) is very effective in making chemotherapy drugs that normally only retard cancer growth, cure 20-60% of mice with different cancer types. These findings have since been confirmed with different cancer types by several other laboratories.

In a recent set of  in vitro experiments, our team tested 18 difference substances used to treat CLL (including commonly used chemotherapy drugs as well as novel and less toxic drugs using the current recommended dose), with and without FMD.

We then combined various cancer drugs and found a combination of three common FDA-approved chemotherapeutic agents, that when given with FMD, succeeded in killing 100% of the CLL cells. 

These three cancer drugs without FMD succeeded in killing around 70% of the CLL cells, which is good but obviously not sufficient for a potentially complete remission of the disease.

As a comparison, none of the 18 agents administered alone, without FMD, achieved more than a 25% kill rate of CLL cells. It is worth noting that the drugs tested included many of the drugs that are currently used to treat CLL patients.

Interestingly, FMD or fasting appears to protect normal cells from the toxic effects of these same agents probably because normal cells switch off the biochemical pathways that these drugs block.  Our earlier studies compared the toxicity of these three agents with and without FMD. The results showed a dramatic decrease in their toxicity to normal mouse cells. Only 10% of cells subjected to the drugs alone survived, but this increased to 75% when the FMD was added.  This exciting result is in agreement with our published work showing high protection in mice and humans undergoing chemotherapy treatment in combination with fasting (Lee C. et al., Sci Transl Med 2012).

So how can a FMD be practically applied to humans? We know of two ways to achieve the desired effects: 1) fasting, and 2) the “fasting mimicking diets” (FMD).  Most patients cannot tolerate fasting for 2-4 days during their chemotherapy sessions so we have developed a FMD that enables a patient to eat “food” while achieving the same effects of fasting on normal and cancer cells. The fasting or FMD is started one day before the therapy and continues for the following 2-3 days while the therapy is most active. Anecdotally, some cancer patients have tested fasting during their chemotherapy and have had fewer side-effects (Safdie et al Aging, 2009). However, this strategy is being tested in at least 9 clinical trials at the USC Norris Cancer Center, Mayo Clinic, Leiden University, University of Genoa, and Charite University, Berlin for both breast and prostate cancer.

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