Team:NJU-China/test
Undeniably, no matter what we pursue, it is the health and wellness that people care about most. Everyone goes for a healthier and stronger body, but we are all clear about that there are numerous diseases around us, and it's still clueless for us to completely resist and cure a large quantity of them. People usually feel uncomfortable and scared by intractable and severe diseases. And cancer must be one of the nightmares.
Cancer is a group of diseases characterized by the uncontrolled growth and spread of abnormal cells. Once the spread, also known as metastasis, isn’t well controlled, it can result in death.[1] As one of the most frightening death threat, cancer can be aggressive and malignant. The harmful effects of cancer on individual, family and society are enormous and appalling.
According to WHO and the latest global cancer statistics (2015), there were 14.1 million new cancer cases in 2012 worldwide and the corresponding estimates for total cancer deaths were 8.2 million (Fig. 1). Literally, about 22,000 cancer deaths happened a day. Besides, 1 in 7 deaths was related to cancer, and cancer caused more deaths than AIDS, tuberculosis and malaria combined. By 2030, the global burden is expected to grow to 21.7 million new cancer cases and 13 million cancer deaths on account of rapid growth and aging of population.[1] Due to the adoption of lifestyles that are known to increase cancer risk, such as smoking, poor diet, physical inactivity and reproductive changes (including lower parity and later age at first birth) in developing country, it’s reasonable to estimate that the actual figures will be considerably larger.[2]
Therefore, cancer is becoming one of the leading causes of death and the major public health problem around the world (Fig. 2).
Cancer statistics describe what happens in large groups of people and provide a picture of the burden of cancer on society. Although statistical trends may not be directly applicable to individual patients, they provide researchers, health professionals, and policy makers with essential information, helping them understand the impact of cancer on population and thus develop appropriate strategies to address the challenges that cancer poses to the society at large. Also, statistical trends are important for measuring the success of efforts in controlling and managing cancer.
2.1 Global cancer statistics
According to the latest Worldwide Cancer Statistics from Cancer Research UK, the top 5 most common cancer sites globally are lung, breast, colorectum, prostate and stomach, with more than 6.9 million new cases reported in 2012[3] (Fig. 3a). Correspondingly, the top 5 most common cancer deaths are lung, liver, stomach, colorectum and breast, accounting for more than half of total cancer death.[4] (Fig. 3b) Over the past 40 years, the most common cancer sites have changed little. Lung, liver, stomach and bowel cancers have been the four most common causes of cancer death since 1975.[5]
More specifically, as noted in Global Cancer Statistics (2015) and Global Cancer Facts & Figures (3rd edition, 2015), worldwide, the top 5 most common cancer in male are lung, prostate, colon & rectum, stomach and liver cancer, while in female, they are breast, colon & rectum, lung, cervix uteri, stomach. And the five most common cancer sites are also the five leading causes of cancer death (Fig. 4).[1] [2]
2.2 Chinese cancer statistics
Cancer incidence and mortality have maintained vigorous growth in China, making cancer the leading cause of death since 2010, corresponding to global trend. Because of China's massive population and difficulties in data collection, previous national estimates were limited and inaccurate. With high-quality data from an additional number of population-based registries now being available through the National Central Center Registry of China (NCCR), it's possible for us to have a general understanding of cancer incidence and mortality in China.
According to Cancer Statistics in China (2015), there were about 4,292,000 newly diagnosed invasive cancer cases in 2015, meaning that almost 12,000 new cancer diagnoses averagely per day. It is estimated that approximately 2,814,000 Chinese died from cancer in 2015, corresponding to more than 7,500 cancer deaths on average per day (Fig. 5)
Two line charts below showed trends of cancer incidence and death rates from year 2000 to 2011, as well as trends of new cancer cases and deaths in China (Fig. 6a, 6b). For all cancers combined, the age-standardized incidence rates were stable from 2000 to 2011 for males, while significant upward trends were observed among females. On the contrary, the age-standardized mortality rates decreased considerably for both sexes. However, it is still worth noting that despite this favorable trend, the number of cancer deaths substantially increased (73.8% increase) during the corresponding period because of the aging and growth of the population.
These striking figures deserve our attention and contemplation, driving us to dig out deeper understanding of cancer, develop appropriate policies for cancer control and design effective treatments for various cancer types.
3.1 Lung cancer statistics
Lung cancer is one of the most frequently diagnosed cancer types and the leading cause of cancer-related death around the world.[7] Globally, an estimated 1.8 million new cases occurred in 2012, accounting for approximate 13% of total cancer diagnoses.[2] An estimated 1.6 million deaths (1.1 million in men and 491,200 deaths in women) were reported in 2012.[1] In some countries, for women, it is now the leading cause of cancer death surpassing breast cancer. The figure below reveals international variation in lung cancer incidence published in Global Cancer Facts & Figures (3rd edition, 2015) (Fig. 7).
Take the United States as an example. According to National Cancer Institute, 224,390 new cases of lung and bronchus cancer are estimated in 2016, accounting for 13.3% of all new cancer cases, in line with the global trends.[8] Despite improvements in surgical techniques and combined therapies over the past several decades, lung cancer is still one of the most lethal cancers. Five-year net survival rate is generally similar worldwide, ranging from 10% to 20%.[1] According to data from SEER 18 2006-2012, present 5-year survival rate of lung cancer in the US is merely 17.7% (Fig. 8).[8] The table below shows 5-year relative surviving of lung cancer from year 1975 to 2008 in the US (Table. 1).
Cancer stage at diagnosis determines treatment options and is strongly related to the length of survival. In general, five-year survival situation will be more optimistic when patients being diagnosed lung and bronchus cancer at an earlier stage. For lung cancer, 15.7% are diagnosed at the local stage, the 5-year survival for which is 55.2%[8] (Fig. 9).
3.2 Basic information of lung cancer
3.2.1 Symptoms, risk factors and classification
Symptoms of lung cancer do not usually occur until the cancer is advanced, and may include persistent cough, sputum streaked with blood, chest pain, voice change, worsening shortness of breath, and recurrent pneumonia or bronchitis. By far, smoking is widely recognized as the primary contributor to lung cancer. And for nonsmokers, passive smoking can be a silent killer. Studies from the US, Europe and the UK have consistently shown significantly increased risk among those exposed to secondhand smoke.[7] Besides, lung cancer is also attributable to increasing age, radon gas, asbestos, air pollution, as well as inherited factors.[1]
Two main categories of lung cancer are classified according to histological types: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). The most common types of NSCLC are squamous cell carcinoma, large cell carcinoma and adenocarcinoma, and all the types can occur in unusual histologic variants. Although NSCLC is associated with smoking, adenocarcinomas may be found in non-smokers. As a class, NSCLC is relatively insensitive to chemotherapy and radiation therapy compared with SCLC.[9]
3.2.2 Treatments of lung cancer
Treatments of lung cancer include surgery, radiation therapy, chemotherapy and targeted therapies, based on types and stages. For early-stage NSCLC, surgery is usually the ideal choice, while chemotherapy, sometimes in combination with radiation therapy, may be given as well. Advanced-stage NSCLC patients are usually treated with chemotherapy, targeted drugs, or some combination of both. Chemotherapy alone or combined with radiation is the usual treatment for SCLC.[10]
Discovery of driver oncogenes has revolutionized the field of lung cancer therapeutics. The identification of distinctive mutations in lung cancer has led to the booming development of molecular targeted therapy. In particular, subsets of adenocarcinoma now can be defined by specific mutations in genes encoding components of the epidermal growth factor receptor (EGFR) and downstream mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-kinases (PI3K) signaling pathways. These mutations may define mechanisms of drug sensitivity and primary or acquired resistance to kinase inhibitors.[10] KRAS-mutant lung cancer accounts for approximately 25% of NSCLC, representing an enormous burden of cancer worldwide. KRAS mutations are frequently observed in adenocarcinoma. Since KRAS mutation in lung cancer was first reported in mid-1980s and remained the most commonly mutated oncogenes in unselected patients, they have risen to fame as elusive targets in a rapidly-evolving field of molecular therapeutics. In the ever-changing world of targeted therapy for molecular drivers of lung cancer growth, KRAS mutations continue to represent a significant challenge for drug development.[11]
Cancer destroy both patients' body and willpower. Traditional therapies for cancers vary from surgery, radiotherapy to chemotherapy.
Surgery is the primary method of treatment for most isolated, solid cancer and may play a role in palliation of pain and prolongation of survival.[12] Namely, feasibility and efficacy of surgery is based on the type and stage of cancer, and for certain types, surgery is far from sufficient to eliminate the cancer.
Radiation therapy is a therapy using ionizing radiation, generally as part of cancer treatment to control or kill malignant cells. It may be curative in a number of types of cancer if they are localized to one area of the body. And it may also be used as part of adjuvant therapy, to prevent tumor recurrence after the surgery to remove a primary malignant tumor. Radiation therapy is synergistic with chemotherapy as well, and has been used before, during, and after chemotherapy in susceptible cancer cases.[13]
Chemotherapy is another conventional cancer treatment that uses one or more anti-cancer drugs, called chemotherapeutic agents, as part of a standardized chemotherapy regimen. It is always given with a curative intent and aims to prolong life or to reduce uncomfortable symptoms.[14]
While radiotherapy and chemotherapy are effective to some extent, the adverse effects remain inevitable, the main kinds of which are fatigue and skin irritation. Acute side effects such as nausea, vomiting, appetite loss, swelling, intestinal discomfort and late side effects such as fibrosis, epilation, dryness and sleeping problem are very common. Immunosuppression, myelosuppression, typhlitis, gastrointestinal discomfort, anemia can also occur after administration of chemotherapy.[15] [16] Since these therapies will inevitably and indiscriminately damage the normal cells, patients always show fragile health condition after treatment, leading to low prognosis.
Nowadays, clinical trials have broadened their ways to immunotherapy, hormone therapy, etc. Take immunotherapy for example: it is one kind of treatment that could induce, enhance, or suppress immune response. Active immunotherapy directs the immune system to attack tumor cells by targeting tumor-associated antigens. Passive immunotherapies enhance existing anti-tumor responses and include the use of monoclonal antibodies, lymphocytes and cytokines.[17] Despite much exiting progress, the therapeutic effect isn’t always satisfactory. Due to the heterogeneity and complexity, tumor cells are good liars playing trick on immune system. Till now, relapse and drug resistance are unable to be avoided effectively and immunotherapy remains controversial and immature. Moreover, it can be very expensive in some cases.
Since cancer is an extremely heterogeneous disease with variants having different genetic and biological properties, drugs targeting a specific molecule that interferes with cancer growth or metastasis are much helpful and effective to ensure that patients will receive optimum management and can be an ideal choice for further exploration. The identification of distinctive mutations in various cancer has led to the booming development of molecular targeted therapy. Small molecule targeted drugs like Gefitinib (Iressa) and Erlotinib (Tarceva) have already been launched into market.[11] However, these drugs have drawbacks as high cost of development and inefficiency due to relatively high off-target rate. Furthermore, their depending on the same chemical entity leads to the difficulty of transplanting to another mutation or cancer case. For instance, Gefitinib, as an EGFR inhibitor, is unable to deal with KRAS mutation in NSCLCs.
In view of serious situation of cancer incidence and mortality, and drawbacks of current treatments, it’s worth developing a much more effective drug system and this is what our project focus on.
Our ideal drug system will contain some basic features as follows:
First, it is designed to be targeting and systemic. Namely, our drug aims at tumor cells and once metastasis appears, it can be a treatment for the whole body as well. In our project, we chose KRAS as our target (插入介绍KRAS的link), and exosome as our delivery agent (插入介绍exosome的link).
Second, precision is one of our goals. To be exact, the targeting peptides on the surface of our delivery agent guarantee the accurate arrival in tumor cells by ligand-receptor interaction. Thus, tumor cell's escape and normal cell's damage will be avoided as much as possible, giving rise to efficiency and minimizing side effects.
In addition, we aim to construct a drug system of high transplantability. There are different types of cancer cases and each case has its distinctive mutations in specific oncogenes. And our system consists of delivery agent (exosome), drug (RNAi) (插入介绍RNAi的link) and targeting tool (iRGD-lamp 2b fusion protein). Hence, it is much easier for us to design a derived drug based on the same silencing and delivery system. By replacing appropriate siRNA and corresponding targeting peptides, it can specifically down-regulate different disease-related genes and thus treat various diseases pertinently. To wit, our drug owns general applicability, leading to remarkable reduce in cost of drug development.
Now you can click three links below to get more detailed information in our drug system.
Target: KRAS
KRAS: A Significant Oncogene
Cancer is caused by alterations in oncogenes, tumor-suppressor genes, and microRNA genes. Oncogenes encode proteins that control cell proliferation, apoptosis, or both. They can be activated by structural alterations resulting from mutation or gene fusion [18].
The two most commonly mutated oncogenes in lung cancer are the epidermal growth factor receptor (EGFR) and KRAS. In terms of EGFR, EGFR mutants were only recently identified, but they have already been established in the clinic as valid predictors of increased sensitivity to EGFR kinase inhibitors (gefitinib and erlotinib). By contrast, even though KRAS mutations were identified in NSCLC tumors more than 20 years ago, the clinic importance of KRAS mutant in cancer therapy just began to be paid more attention. Recent studies show that lung cancer patients with KRAS mutant do not respond to either EGFR inhibitor or adjuvant chemotherapy. Therefore, KRAS-targeting therapeutics are sorely needed [19].
K-ras protein is a small GTPase (~21 kDa) encoded by KRAS gene [20]. K-ras possesses an essential role in normal tissue signaling. It can be activated by signals from cell surface receptors, subsequently switches on other proteins and ultimately turns on genes, turning on genes involved in cell growth, differentiation, and survival. K-ras uses a bound guanine nucleotide (GDP/GTP) to toggle between its “on” and “off” states. It binds GDP in its neutral state. When a signal arrives, GTP will take place of GDP with the help of guanine nucleotide exchange factors (GEFs), causing a rearrangement of the protein, thus, switching itself “on” to deliver the signal to the final destination [21]. Normally, K-ras has an intrinsic ability to hydrolyze GTP transiently and turn itself “off”. Mutations of KRAS oncogene lead to a strongly reduced GTPase activity of K-ras protein, making KRAS stay at a constitutively activated “on” state. Thereby, the signal is passed continuously, allowing the cell to proliferate without control [22].
KRAS in Lung Cancer
The two main types of lung cancer are non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) [23]. NSCLC accounts for about 85% of lung cancers. As a class, NSCLCs are relatively insensitive to chemotherapy, compared to small cell carcinoma. Lung adenocarcinoma is the most common subtype of NSCLC, and it accounts for approximately 40% of lung cancers [24].
It has been found that the activation of the KRAS oncogene is specifically associated with the histological features of adenocarcinoma and does not or rarely occur in other types of NSCLC [26]. Approximately 15–25% of the patients with lung adenocarcinoma have tumor-associated KRAS mutations. In the majority of cases, these mutations are missense mutations which introduce a single amino acid substitution at position 12, 13, or 61. The result of these mutations is constitutive activation of KRAS signaling pathways [27]. In the vast majority of cases, KRAS mutations are found in tumors with wild type for EGFR or ALK; in other words, they are non-overlapping with other oncogenic mutations found in NSCLC. Therefore, KRAS mutation defines a distinct molecular subset of the disease.
Clinical Importance
far the most important single prognostic factor. But the role of KRAS as either a prognostic or predictive factor in NSCLC still remains mostly unclear at the moment [29].
The KRAS point mutation may not only be valuable as a prognostic marker. Valiant attempts have been made to develop cancer therapeutics targeting mutant KRAS signaling. However, to date, there are no direct anti-KRAS therapies available.
The therapeutic potential of systemically delivered RNAi had been demonstrated as a novel treatment for cancer. Thanks to many prominent advantages like nontoxicity and targeting, KRAS siRNA delivery is a promising choice for further drug development.
[1] Global Cancer Facts & Figures (3rd edition), 2015. American Cancer Society.
[2] Lindsey A. Torre, Freddie Bray, Rebecca L. Siegel, Jacques Ferlay, Joannie Lortet-Tieulent, Ahmedin Jemal. Global Cancer Statistics, 2012. CA CANCER J CLIN. 2015; 00:
[3] Worldwide Cancer Incidence. International Agency for Research on Cancer of WHO and Cancer Research UK.
[4] Worldwide Cancer Mortality. International Agency for Research on Cancer of WHO and Cancer Research UK.
[5] Worldwide cancer mortality statistics. Cancer Research UK. http://www.cancerresearchuk.org/health-professional/cancer-statistics/worldwide-cancer/mortality
[6] Wanqing Chen, Rongshou Zheng, Peter D. Baade, Siwei Zhang, Hongmei Zeng, Freddie Bray, Ahmedin Jemal, Xue Qin Yu, Jie He. Cancer Statistics in China, 2015. CA CANCER J CLIN. 2016; 66:115–132.
[7] Lung cancer. Wikipedia. https://en.wikipedia.org/wiki/Lung_cancer
[8] Cancer Statistics. National Cancer Institute. https://www.cancer.gov/about-cancer/understanding/statistics
[9] Fact Sheets About Lung and Bronchus Cancer. National Cancer Institute. http://seer.cancer.gov/statfacts/html/lungb.html
[10] Non-Small Cell Lung Cancer Treatment (PDQ®)–Health Professional Version. National Cancer Institute. https://www.cancer.gov/types/lung/hp/non-small-cell-lung-treatment-pdq
[11] Admir Ahmad, Shirish Gadgeel. Lung Cancer and Personalized Medicine. Springer, 2016; 127, 155-156, 172-173.
[12] Cancer. Wikipedia. https://en.wikipedia.org/wiki/Cancer
[13] Radiation therapy. Wikipedia. https://en.wikipedia.org/wiki/Radiation_therapy
[14] Chemotherapy. Wikipedia. https://en.wikipedia.org/wiki/Chemotherapy
[15] Cancer Treatment. National Cancer Institute. https://www.cancer.gov/about-cancer/treatment
[16] Side Effects. National Cancer Institute. https://www.cancer.gov/about-cancer/treatment/side-effects
[17] Cancer immunotherapy. Wikipedia. https://en.wikipedia.org/wiki/Cancer_immunotherapy
