Identifying and Targeting Autophagy Dependence to Eliminate Metastatic Breast Cancer

Principal Investigator: THORBURN, ANDREW M
Institution Receiving Award: COLORADO, UNIVERSITY OF, AT DENVER
Program: BCRP
Proposal Number: LC110302
Award Number: W81XWH-14-1-0185
Funding Mechanism: Breakthrough Award - Funding Level 2 - Partnering PI Option
Partnering Awards:
Award Amount: $565,053.00


Breast cancer is a leading cause of cancer-associated death in women in the United States. The majority of these deaths result from uncontrolled metastatic disease as current therapies, including surgery, hormone therapy, chemotherapy, radiation therapy, and selective combinations are not completely effective in the treatment of metastatic breast cancer. Sadly, these therapies do not prevent the development of estrogen receptor-negative breast cancer, which is more aggressive with high recurrence, metastatic, and mortality rates, and unfortunately not sensitive to anti-estrogen therapy, such as tamoxifen and aromatase inhibitors. The inability to effectively predict, prevent, and treat metastatic breast cancer is a major problem in breast cancer care. Therefore, development of additional effective targeted therapies are urgently needed, and understanding the basic mechanisms involved is required in order to find safer and more effective treatments to decrease breast cancer metastasis and recurrence. Weight increase and obesity has drastically increased in the last decades and are important risk and prognostic factors for breast cancer in postmenopausal women. Chronic inflammation induced by obesity correlates with increased appearance of aggressive, chemotherapy-resistant breast cancer (TNBC), breast cancer recurrence, and metastasis.

The fundamental basis of this proposal is the growing evidence from my lab and many others that sphingosine-1 - phosphate(S1P), a bioactive sphingolipid signaling molecule formed inside cells by enzymes called sphingosine kinases, regulates many physiological processes involved in obesity, inflammation, and cancer. Patients with breast cancer have elevated levels of sphingosine kinase that correlates with poor prognosis.However, how sphingosine kinases and S1P regulate human cancer is not known.A deeper understanding of the mechanisms of the cancer risk posed by sphingosine kinases could uncover new strategies for countering these risks.Our research will reveal that S1P and the sphingosine kinases that produce it are critical bridges between obesity - associated chronic inflammation and breast cancer.This could connect two exceptionally important cancer research disciplines and lead to new therapeutic targets and new drug development for breast cancer. Our overarching goal is to develop new therapies for the treatment of obesity promoted breast cancer and TNBC that can then be taken into the clinic.

To do this, we are developing a novel concept for the treatment and perhaps prevention of metastatic breast cancer using the drug FTY720(fingolimod, trade name Gilenya).FTY720 has many advantages for cancer treatment. First, it has already passed numerous clinical trials in humans and been approved by the U.S.Food and Drug Administration and the European Medicines Agency for the treatment of multiple sclerosis, thus decreasing the time it would take to begin clinical trials for breast cancer treatment.The drug can be taken orally, stays in the body for significant periods of time, and has a low incidence of manageable side effects.Importantly, we found that FTY720 has multiple anti - cancer activities and it prevents formation and actions of S1P.Moreover, it can enhance sensitivity of advanced and hormonal refractory breast cancer and TNBC to conventional therapies.

Our proposal will demonstrate that S1P signaling is a critical factor that links obesity, chronic inflammation, and breast cancer development, and we will show that FTY720 can break these links and has promise as a new adjuvant therapy.Ultimately, our goal is to develop therapies to reduce, and perhaps prevent, metastasis and decrease breast cancer mortality, particularly for the hard-to - treat, therapy - resistant, estrogen receptor - negative breast cancer and TNBC patients.