Cancer is the second leading cause of death in the United States.1 Some of the most commonly diagnosed malignancies in the US are cancers of the lung, breast, and gastrointestinal tract (colorectal, pancreas, liver, stomach).1,2 Although recent advances in prevention, detection, and treatment have led to a decline in death rates for lung, breast, and colorectal cancers, their prevalence remains high.1 The high mortality associated with these cancers, particularly lung, pancreas and liver, demonstrate the need for more effective treatment options.
The Wnt pathway is a primary physiological regulator and signaling pathway that controls the activity of stem cells. These specialized cells have unique abilities to self-renew and form multiple cell types and tissues.3 Altered expression or activity of various Wnt pathway components through DNA mutations or epigenetic changes in stem or normal cells can cause Wnt signaling to be inappropriately activated, resulting in transformation, proliferation, and replicative immortality of cells.3,4 Therefore this pathway, which is normally tightly regulated, can become hijacked in malignant tumors and contribute to cancer development and progression.3-5 As evidence of this, medical research to date has discovered aberrant activation of Wnt signaling in many cancer types. Therefore, targeted modulation of the Wnt pathway with small-molecule drugs offers a potential therapeutic option for the treatment of a broad range of cancers.
Lung cancer is the leading cause of cancer death and the second most diagnosed cancer in both men and women in the United States. The number one cause is cigarette smoking, but it can also be caused by environmental exposure to substances such as asbestos and radon, and occurs more frequently in persons with a family history of lung cancer. Since spiking in the mid 1980’s, the incidence rate has been in decline due to a decrease in tobacco smoking.1,2
- There will be an estimated 222,500 new cases of lung cancer in 2017 in the US, equaling 13.2% of new cancer cases.1,2
- In 2017 it will be responsible for an estimated 155,870 cancer deaths.1
- After diagnosis, only 18.1% of patients will survive 5 years or more.2
- Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer diagnoses.1
Available evidence suggests that increased Wnt signaling plays a role in tumor development, aggressiveness, and treatment resistance in lung cancer. Although genetic mutations in the Wnt pathway are uncommon in NSCLC, activated Wnt signaling is present in most NSCLC cell lines and tumor samples, indicating that epigenetic changes are responsible.6
- Several components of the Wnt pathway that drive activation may be overexpressed in NSCLC, and loss of expression or activity of various endogenous Wnt pathway inhibitors has frequently been observed in NSCLC cell lines and resected tumors, suggesting that upregulation of Wnt activity can occur in multiple ways.6
- Treatment-induced inhibition of specific Wnt pathway activators, or restored expression of endogenous inhibitors decreases proliferation and induces cell death in NSCLC cell lines.6
- NSCLC cells with activated Wnt signaling are resistant to chemotherapy and radiation.6
Breast cancer (female) is the most frequently diagnosed cancer in the US, and the second-leading cause of cancer death among women. Although the vast majority of breast cancer causes are not linked to hereditary genetic mutations, women who inherit mutations in the BRCA1 or BRCA2 genes have a significantly increased risk of developing breast cancer. Importantly, 80% of women who get breast cancer do not have a family history of the disease. Improvements in early detection and treatment have led to a decline in breast cancer deaths since the peak in 1989.1,2 About 10-20% of breast cancers are found to test negative for estrogen receptors (ER-), progesterone receptors (PR-), and HER2 (HER2-) meaning the cancer is triple-negative. Triple-negative breast cancer does not respond to hormonal therapy (such as tamoxifen or aromatase inhibitors) or therapies that target HER2 receptors (trastuzumab).7
- There will be an estimated 252,710 new cases of female breast cancer diagnosed in 2017, equaling 15% of total cancer diagnoses in women and 2470 in men in the US.1,2
- In 2017, it will be responsible for an estimated 41,070 deaths.1
- After diagnosis, 89.7% of patients will survive 5 years or more.2
- In 2014, there were an estimated 3,327,552 women living with breast cancer in the US.2
Several studies have demonstrated evidence of activated Wnt signaling in breast cancer.8
- Approximately 50% of breast cancer samples show activated Wnt signaling, and this is linked to reduced overall survival.8
- Wnt signaling pathway components are often overexpressed in breast cancers, and endogenous pathway inhibitors are downregulated.8
- Animal models of breast cancer showed that Wnt activity was necessary for tumor growth.8
Colon and rectum cancer is the second leading cause of cancer death in the US among men and women combined, and is the third most common cancer in both men and women. Lifestyle-associated risk factors include obesity, physical inactivity, smoking, and diet. A family history of colorectal cancer or polyps also increases risk.1,2
- There will be an estimated 135,430 new cases diagnosed in 2017, equaling 8% of all new cancer cases.1,2
- In 2017, it will be responsible for an estimated 50,260 deaths.1
- In 2014, there were an estimated 1,317,247 people living with colon and rectum cancer in the US.2
The association between aberrant Wnt pathway activity and colorectal cancer is well documented.9,10
- Genetic alterations in the Wnt signaling pathway have been identified in colorectal carcinoma.10
- 81% of colorectal tumor samples harbored mutations in the APC tumor suppressor gene alone, which is a key component and regulator of the Wnt signaling pathway.11
Liver cancer incidence has tripled since 1980, and this rate has increased by about 4% per year in recent years. It is 3 times more common in men than women. Risk factors for developing liver cancer in the US are chronic infection with hepatitis B and/or hepatitis C virus, heavy alcohol consumption, obesity, diabetes, and tobacco smoking. Rare genetic disorders also impart risk.1,2
- There will be an estimated 40,710 new cases of liver cancer in the US in 2017, equaling 2.4% of all cancer diagnoses.1,2
- In 2017 it will be responsible for 28,920 cancer deaths.1
- After diagnosis, only 17.6% of patients will survive for 5 or more years.2
- Hepatocellular carcinoma (HCC) will be the diagnosis for 75% of new cases.1
Alterations in Wnt pathway genes through mutation or epigenetic changes are common in liver cancers, particularly HCC, which points to dysregulation of Wnt signaling as a contributing factor to cancer development and/or progression.9,12
- Up to 90% of HCC samples show evidence of Wnt pathway activation, and 54% of HCC cases had specific alterations in the Wnt signaling pathway.12,13
- Mutations in genes that encode 2 important Wnt pathway proteins, the downstream activator of Wnt signaling, and a signaling regulator that serves as a tumor suppressor, are commonly found in HCC cell lines and samples.9,13
- Increased Wnt signaling in HCC may also be due to epigenetic (without gene mutation) silencing of normally occurring Wnt pathway inhibitors, which is frequently found in HCC tumors.9,12
Pancreatic cancer is the fourth leading cause of cancer death in both sexes. Symptoms do not usually appear until the cancer has progressed, which contributes to the high mortality rate. Risk factors include cigarette smoking, obesity, diabetes, excessive alcohol consumption, and a family history of pancreatic cancer.1,2
- There will be an estimated 53,670 new cases of pancreatic cancer in the US in 2017, equaling 3.2% of all cancer diagnoses.1,2
- In 2017, it will be responsible for an estimated 43,090 deaths or 7.2% of all cancer deaths.1
- After diagnosis, only 8.2% of patients will survive 5 years or more.2
Substantial evidence demonstrates involvement of activated Wnt signaling in pancreatic cancer.14
- Aberrant Wnt pathway activation is seen in 65% of advanced pancreatic adenocarcinomas.14
- Analysis of circulating pancreatic cancer cells revealed increased Wnt signaling in these cells, which may contribute to metastasis15
- Genome wide analysis of pancreatic tumors revealed that Wnt pathway genes often carry mutations or are epigenetically altered16
Stomach cancer is the 15th most commonly diagnosed cancer by site in the US. Men are nearly twice as likely as women to develop stomach cancer. Other risk factors include obesity, heavy alcohol consumption, and infection with Heliobacter pylori.1,2
- There will be an estimated 28,000 new cases of stomach cancer in the US in 2017, equaling 1.7% of all cancer diagnoses.1,2
- In 2017, it will be responsible for an estimated 10,960 deaths (1.8% of all cancer deaths).1
- After diagnosis, 30.6% of patients will survive 5 years or more.2
Evidence of aberrant activation of the Wnt signaling pathway has been demonstrated in stomach cancer, and may be involved in disease development and progression.17
- Activated Wnt signaling has been found in more than 30% of gastric cancers.17
- Mutations in key genes of the Wnt pathway may be driver mutations (i.e., early mutations that initiate cancer development) in gastric cancers.17
- Preclinical studies show that H. pylori may cause stomach cancer through interactions with the Wnt pathway.17
- American Cancer Society. Cancer Facts &Figures 2017. Atlanta: American Cancer Society; 2017
- Howlader N, Noone AM, Krapcho M, et al. (eds). SEER Cancer Statistics Review, 1975-2014, National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/csr/1975_2014/, based on November 2016 SEER data submission, posted to the SEER web site, April 2017.
- Clevers H & Nusse R. Wnt/β-catenin signaling and disease. Cell. 2012;149(8): 1192-1205.
- Hanahan D, Weinberg R. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-74.
- de Sousa EM, Vermeulen L, Richel D, Medema JP. Targeting Wnt signaling in colon cancer stem cells. Clin Cancer Res. 2011;17(4):647-53.
- Stewart DJ. Wnt signaling pathway in non-small cell lung cancer. J Natl Cancer Inst. 2014; 106(1):djt356.
- www.breastcancer.org/symptoms/diagnosis/trip_neg. Accessed September 19, 2017
- Lin SY, Xia W, Wang JC, Kwong KY, Spohn B, Wen Y et al. Beta-catenin, a novel prognostic marker for breast cancer: its roles in cyclin D1 expression and cancer progression. Proc Natl Acad Sci USA 2000; 97: 4262–4266.
- Polakis P. Wnt signaling in cancer. Cold Spring Harb Perspect Biol. 2012;4:a008052.
- Zhan T, Rindtorff N, Boutros M. Wnt signaling in cancer. Oncogene. 2017;36:1461-73.
- The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(July19):330-7.
- Thompson MD, Monga SPS. Wnt/β-catenin signaling in liver health and disease. Hepatology. 2007;45:1298-1305.
- Schulze K, Imbeaud S, Letouze E, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet. 2015;47(5):505-11.
- Zeng G, Germinaro M, Micsenyi A, et al. Aberrant Wnt/beta-catenin signaling in pancreatic adenocarcinoma. Neoplasia. 2006;8(4):279-89.
- Yu M, Ting DT, Stott SL, et al. RNA sequencing of pancreatic circulating tumour cells implicates WNT signalling in metastasis. Nature. 2012 Jul 26;487(7408):510-3.
- Sahin B, Iacobuzio-Donahue, O’Reilly EM. Molecular signature of pancreatic adenocarcinoma: an insight from genotype to phenotype and challenges for targeted therapy. Expert Opin Ther Targets. 2016;20:341-59.
- Chiurillo MA. Role of the Wnt/β-catenin pathway in gastric cancer: an in-depth literature review. World J Exp Med. 2015;5(2):84-102.