Programs

In 2015, the Bonnie J. Addario Lung Cancer Foundation (ALCF) will focus on funding the following urgent unmet medical needs in the field of lung cancer, to take us to our goal of making lung cancer a chronically manageable disease by 2023.

Early detection modalities for lung cancer- One of the leading factors for lung cancer being the #1 cancer killer is the advanced stage at the time of diagnoses when the disease has progressed and metastasized beyond the primary site of the lungs. The five-year survival rate for lung cancer is 53.5 percent for cases detected when the disease is still localized within the lungs. Unfortunately, only 15 percent of lung cancer cases are diagnosed at an early stage [1]. Though smoking cessation measures will impact lung cancer incidence and mortality rates, a majority of new lung cancer diagnoses are in former smokers, and to some extent in never-smokers. Therefore, ALCF seeks novel, minimally invasive strategies that detect malignant lesions at an earlier stage in all patient demographics (smokers, former smokers, never-smokers), thereby impacting quality of life as well as improving survival of lung cancer patients.

Identification of validated risk/diagnostic/prognostic lung cancer biomarkers to

• improve the selection of high-risk individuals for CT screening, i.e. patient risk stratification;
• distinguish benign lesions from malignant nodules;
• identify disease relapse/recurrence before it is clinically apparent

Advances in multiple high-throughput “-omics” technologies (genomics, epigenomics, proteomics, metabolomics) allow the identification of unique biomarkers that can report disease recurrence before its physiological manifestation. Non-invasive identification of these diagnostic and prognostic biomarkers in blood, urine, exhaled breath condensate, bronchial specimens, saliva, and sputum is critical for reducing lung cancer mortality and improving the quality of life of patients with the disease. An ideal biomarker should

• be quantifiable and reproducible,
• have good testing performance [with good positive predictive value (PPV) and negative predictive value (NPV)],
• be measurable in accessible material, in small amounts and with little preparation,
• indicate a disease state,
• have proven clinical use,
• be adopted by the community-at-large to take advantages of the benefits testing affords, be cost-effective; and
• be reimbursed by health insurers.

Previous studies have validated the benefit to employing multiple biomarkers in a combinatiorial panel to bypass the need for multiple patient specimens as well as identifying all underlying abnormalities in one test, considering both intra- as well as inter-tumoral heterogeneity.

ALCF seeks novel research proposals that aim to identify and validate suitable biomarkers that either, individually, or preferably in combination are valuable for patient risk stratification as well as serve predictive, diagnostic and prognostic purposes.

Small Cell Lung Cancer (SCLC): Small cell lung cancer accounts for 10-15% of all lung cancer diagnoses and claims over 160,000 lives each year in the United States alone. A very aggressive form of lung cancer with a median survival of less than two years, SCLC currently does not have any targeted therapies approved.

ALCF will focus on funding research that looks at the following aspects associated with SCLC:

• Novel model systems to study the disease
• Unique biomarkers that allow early detection
• Specific genetic abnormalities in SCLC and therapeutic modalities to target these.

What are the underlying causes for the gender differences in lung cancer incidence and mortality?

Lung Cancer is the #1 cancer killer in women:

• An unfortunate and often unknown fact is that lung cancer is the leading cancer killer in women. In 2012, the 209,000 deaths in developed countries from lung cancer in women far outnumbered the 197,000 deaths from breast cancer.
• While deaths in the United States from breast cancer are expected to be slightly more than 40,000 in 2015, female deaths from lung cancer are predicted to be over 71,000 [2].
• Although breast cancer diagnosis is twice as common in women (1 in 8 women will get breast cancer) compared to lung cancer (1 in 16 women), the cure rate for lung cancer is much lower, resulting in more deaths from lung cancer.

Why are more women being diagnosed with lung cancer?

• Several studies have indicated that women are more susceptible to developing lung cancer than men.
• Female smokers are twice as likely to develop lung cancer as male smokers, even when they smoke fewer cigarettes over a shorter period of time.
• Even among non-smokers, the risk of developing lung cancer is higher among women than men: 1 in 5 women who develop lung cancer have never smoked, whereas 1 in 12 men diagnosed with lung cancer have never smoked.
• Women lung cancer patients are, on an average, younger than male patients.

The reasons for these gender differences in lung cancer incidence, risk factors, histology, pathophysiology, treatment outcomes, prognoses etc. are still unclear. 
ALCF would like to investigate these aspects in further detail to identify why women are increasingly being diagnosed with aggressive lung cancer.

Some studies suggest that female hormones, estrogen and progesterone, may play a part in the development of lung cancer among women.

Role of hormones in the development of lung cancer- It is unclear why non-smoking women are at greater risk for developing lung cancer than non-smoking men. Studies indicate that biological and genetic differences between men and women play a role in susceptibility to lung cancer and the risk of dying from it. Some research shows that estrogen, a hormone found in both men and women but much higher in women, may help certain lung cancer cells to grow and spread throughout the lungs. For example, a 2009 study based on the Women’s Health Initiative showed that post-menopausal women who took estrogen and progesterone combined hormone therapy had an increased risk of dying from lung cancer, regardless of whether they had never smoked, stopped smoking, or were currently smoking (although current and former smokers were at the highest risk for death) [3]. A 2010 study indicated that post-menopausal women who took hormone therapy for more than 10 years were at an increased risk of developing lung cancer [4]. In 2011, a study showed that women who take estrogen-blocking medication like tamoxifen to prevent a recurrence of breast cancer also reduce their risk of dying from lung cancer [5]. For both the 2010 and 2011 studies, the link between hormones and lung cancer were maintained regardless of the person’s smoking status.

Pre-clinical data: Researchers have looked into estrogen and progesterone receptors in lung cancer in both lung cancer–derived human cell lines and in actual tumor specimens from patients and found estrogen receptor expression in the lung cancers. In mouse studies where ovariectomized mice were treated with estradiol, the mice also developed lung cancer, and when they were given anti-estrogens it reversed the process. Based on the data from the mouse studies and early laboratory studies, it looks like estrogen does affect lung cancer, so there is some biologic explanation.

Estrogen Receptor (ER): Though the presence of estrogen receptors (ERs) in human lung tissue has been controversial for many years, it has been proved beyond doubt that some forms of both ERα and ERβ are indeed present in normal lung cells as well as in lung tumors, which are undeniably functional, as evidenced by the estrogen-induced cell proliferation in the lung in vitro as well as in vivo; activation of transcription from estrogen response elements (ERE) in lung cancer cells by estrogen and estrogen-stimulated secretion of a growth factor thought to be involved in lung tumorigenesis, collectively demonstrating that ERs play a biological role in the lungs.

Female hormones influence lung carcinogenesis but the precise mechanisms are unclear. Further investigation of the pathophysiology of female hormones in lung cancer subtypes and their interaction with smoking will lead to a better understanding of lung carcinogenesis.

What is the impact of factors such as age at menopause, age at menarche, age at first birth, postmenopausal use of hormone replacement therapy, and past oral contraceptive use on the initiation and progression of lung cancer in women?

Lung Cancer Causative factors in Non-smokers- Each year in the United Staes alone, approximately 16,000 to 24,000 deaths are attributed to lung cancer in never smokers [6]. In fact, if lung cancer in never-smokers is considered a separate category, it currently ranks as the sixth most fatal cancer in the United States. Lung cancer in never smokers is a completely different disease at the molecular level as well as in its response to therapy compared to lung cancer in smokers/ former smokers, however, it is treated the same way as the latter. Further, it is typically diagnosed at a late stage because of the general perception that lung cancer is only caused by smoking. Though a few environmental factors have been attributed to carcinogenesis in non-smokers, such as exposure to radon, asbestos, secondhand smoke etc., a large fraction of never-smoker lung cancer remains without established etiology. Therefore, the ALCF seeks proposals that will address this significant public health problem through carefully designed studies in well-defined populations, with specific aims to identify the mechanisms of oncogenesis, disease progression and targeted therapeutics for this category of lung cancer patients.

Are viruses an etiological agent for lung cancer? Several studies have shown an association between the Human Papilloma Virus (HPV), an etiological agent for genital cancers, and lung cancer, especially in never smokers, prompting speculation that HPV might be one of the causes of tumorigenesis in non-smokers. However, most of these studies are association-based epidemiological reports. There are currently no studies that unequivocally prove that HPV is a lung cancer causative agent. If proven, this might allow the development of specific therapies for this subset of patients. Studies into the precise mechanisms governing the processes by which HPV gains access to the lung tissue, the specific underlying molecular and/or genetic aberrations it causes that lead to tumor initiation and progression need to conducted to establish an infectious origin for this subset of lung cancer.

Attacking Lung Cancer using Combination Therapies

References:

1. U.S. National Institutes of Health. National Cancer Institute: SEER Cancer Statistics Review, 1973-2010.
2. American Cancer Society. Cancer Facts & Figures 2015. Atlanta: American Cancer Society; 2015.
3. Chlebowski RT, et al.  Oestrogen plus progestin and lung cancer in postmenopausal women (Women’s Health Initiative trial): a post-hoc analysis of a randomised controlled trial. Lancet. 2009;374(9697):1243-1251.
4. Slatore CG, et al. Lung cancer and hormone replacement therapy: association in the vitamins and lifestyle study. J Clin Oncol. 2010;28(9):1540-1546.
5. Bouchardy C, et al. Lung cancer mortality risk among breast cancer patients treated with anti-estrogens. Cancer. 2011;117(6):1288-1295.
6. Samet, JM et al. Lung cancer in never smokers: Clinical epidemiology and environmental risk factors. Clin Cancer Res. 2009; 15(8): 5626-5645.