Project description

According to the World Health Organization, Colorectal cancer (CRC) accounts for approximately 10% of all annually diagnosed cancers and cancer-related deaths worldwide. It is the second most common cancer diagnosed in women and third most in men. In women, incidence and mortality are approximately 25% lower than in men. These rates also vary geographically, with the highest rates seen in the most developed countries (Dekker et al., 2019). With continuing progress in developing countries, the incidence of colorectal cancer worldwide is predicted to increase to 2.5 million new cases in 2035(Kijima et al., 2014). Genetic, lifestyle, obesity, and environmental factors might have some association with CRC. Colon cancer patients could suffer from the symptom of blood in or on their faeces （which brings a sharp pain to one’s rectum, anus, and large intestine. The blood remnants in one’s rectum could incur to severe obstacles to one’s health. Furthermore, Diarrhea, constipation, abdominal pain, aches, or cramps that remain permanently could all be directly caused by colon cancer. The harm of colorectal cancer forms a vicinity around the human population and persists to establish turmoil and mental and physical annihilation to the society.

Current treatments include endoscopic and surgical local excision, downstaging preoperative radiotherapy and systemic therapy, extensive surgery for locoregional and metastatic disease, local ablative therapies for metastases, and palliative chemotherapy, targeted therapy, and immunotherapy.

Chemotherapy:The conventional treatment for cT3-T4 or node-positive clinically resectable rectal cancer is long course preoperative chemoradiation followed by surgery and postoperative adjuvant chemotherapy. Disadvantages of this approach include possible overtreatment of patients, 6 weeks of daily radiation treatment, and undetected metastatic disease. There are a number of emerging trends which are changing this approach to treatment. Selected topics included in this manuscript include the selective use of pelvic radiation, the role of radiation for a positive radial margin, the interval between radiation and surgery, non-operative management, new chemoradiation regimens, short vs. long course radiation, and the role of postoperative adjuvant chemotherapy.

Surgery: Since the emergence of minimally invasive technology twenty years ago, as a surgical concept and surgical technique for colorectal cancer surgery, its obvious advantages have been recognized. Laparoscopic technology, as one of the most important technology platform, has got a lot of evidence-based support for the oncological safety and effectiveness in colorectal cancer surgery Laparoscopic technique has advantages in terms of identification of anatomic plane and autonomic nerve, protection of pelvic structure, and fine dissection of vessels. But because of the limitation of laparoscopic technology there are still some deficiencies and shortcomings, including lack of touch and lack of stereo vision problems, in addition to the low rectal cancer, especially male, obese, narrow pelvis, larger tumors, it is difficult to get better view and manipulating triangle in laparoscopy. However, the emergence of a series of new minimally invasive technology platform is to make up for the defects and deficiencies. The robotic surgical system possesses advantages, such as stereo vision, higher magnification, manipulator wrist with high freedom degree, filtering of tremor and higher stability, but still has disadvantages, such as lack of haptic feedback, longer operation time, high operation cost and expensive price.

Hormone therapy:Satraplatin is a novel, orally bioavailable, platinum anticancer drug. Platinum analogs form the mainstay of treatment for a number of cancers, including lung, ovarian, colorectal and head and neck cancer. A disadvantage of the currently marketed platinum analogs is that they must all be administered via intravenous infusion. In addition, their utility is often limited by toxicity, particularly neurotoxicity, ototoxicity and renal toxicity. Satraplatin has preclinical antitumor activity comparable with that of cisplatin and, clinically, has a more manageable side-effect profile. Satraplatin is active in lung, ovarian and prostate cancer, and appears to have good efficacy in combination with radiation for lung and head and neck cancer. Preclinical data suggest it may also be effective for the treatment of certain cisplatin-refractory tumors. 

Target therapy:Targeted therapy is a term for agents directed at unique biological features of cancers rather than agents that kill cells as they replicate, including both cancer cells and others. In theory, turning off a dominant pathway with a precise antagonist should optimize the balance between tumor cell killing and off-target effects such as bone marrow and epithelial cell damage. Because patients with mCRC can sometimes be cured with combinations of systemic treatment and surgery, added efficacy could make a major difference in outcomes. Unfortunately, although the RAS pathway is dominant in approximately 40% to 50% of patients with mCRC,10 there are numerous specific mutations within the RAS family that may drive cancer progression in a given patient. Therefore, even if, for example, the excitement recently engendered by new agents with an inhibitory effect on a K-RAS-12C–mutated preclinical mCRC model11 is affirmed in clinical trials, the impact will likely be limited to the 4% or so of patients whose tumors harbor that precise mutation.11 Arguably, until the mystery of RAS is solved, targeted therapies for bio-marker-selected patients with mCRC may improve outcomes on the margins but are not likely to dramatically change treatment paradigms for the majority of patients(Piawah and Venook, 2019).

Therefore, the development of a new, highly accurate, and efficient treatment is essential for the detection of CRC in clinical practice. 

Cancer therapy has seen significant advancements in recent years, with the emergence of RNA interference (RNAi) as a promising strategy for targeted gene silencing(Dong et al., 2019). siRNA is a 19-23 base pair nucleotide sequence designed to reach the cell cytoplasm and once there, binds with the RNA-induced silencing complex (RISC). Binding with the RISC leads to degradation of the sense strand, whereas the antisense strand continues to be incorporated in the RISC. The RISC then makes multiple mRNA cleavages to downregulate single gene expression (Fig. 2).

RNAi therapy, with delivering exogenous siRNAs into tumors, brings gene regulation into clinical practice and interest in siRNA therapy has grown and expanded in scope over the past decade. Some promising results about siRNA therapy in Acute lymphoblastic leukemia (ALL) patients.A cyclodextrin-based cationic polymer was designed to successfully deliver siRNA against to ribonucleotide reductase (RRM2) for various in vivo cancer-related models (Heidel et al., 2007).Several siRNA-based drugs are undergoing clinical trials, and one drug patisiran (Onpattro) is approved for use in the clinic.This drug is consisted a siRNA against TTR in complex with a cationic lipid, cholesterol, phospholipid, and a conjugate of lipid and polyethylene glycol. Moreover, siRNA could also be applied to target genes and signaling pathways related to CRC tumorigenesis.

siRNA has innate advantages over small molecular therapeutics and monoclonal antibody drugs because siRNA executes its function by complete Watson–Crick base pairing with mRNA, whereas small molecule and monoclonal antibody drugs need to recognize the complicated spatial conformation of certain proteins. As a result, there are many diseases that are not treatable by small molecule and monoclonal antibody drugs since a target molecule with high activity, affinity and specificity cannot be identified. In contrast, theoretically, any gene of interest can be targeted by siRNA since only the right nucleotide sequence along the targeting mRNA needs to be selected. This advantage confers the siRNA modality with a shorter research and development spanand a wider therapeutic area than small molecule or antibody drugs, especially for those genes that are unfeasible for development with such strategies(Gencer et al., 2021). The synthesis of antisense nucleotides is also relatively easy and cheap. Moreover, another significant advantage of antisense reagents over the small molecule drugs is that they possess the capability of silencing the multidrug resistance (MDR) gene whenever cell develops MDR drug resistance. Ultimately, siRNA therapy has the potential to revolutionize treatments and improve patient outcomes.

Based on the above information, our project aim at constructing novel biotherapeutics through siRNA for improving patient treatment of CRC. The HIPPO pathway is a key regulatory pathway in tumor development, with TEAD4 being a core transcription factor that promotes the growth and spread of CRC cancer cells(Guo et al., 2022). Moreover, TEAD4 was upregulated in tumor tissues compared to paracancerous tissue (Song et al., 2023). Therefore, interfering with the function of TEAD4 is considered an effective strategy to inhibit tumor growth.

We designed siRNAs targeting at TEAD4. Theoretically, when the siRNAs were transfected into tumor cells, the TEAD4 expression was inhibited. TEAD4 expression could affect downstream HIPPO pathway, which promotes the growth and spread of various tumors. Threrefore, when CRC cells were treated with siRNAs, the proliferation, migration and invasion ability were inhibited. The tumor cells tend to lose the cancer cell character after siRNA treatment, which are expected to achieve favorable curative effect in clinical practice.

This mechanism holds promise for the bioengineering of therapeutics for CRC, analogous to how numerous targeted cancer therapeutics have arisen from comparable investigational frameworks. The assay is designed to be uncomplicated, with high sensitivity and specificity, utilizing laboratory-derived plasmids and cell lines. The assay can be executed within a fortnight. Although the specificity of the test may entail higher expenses, it is anticipated that an increasing number of CRC patients will profit from this research in the future. The development of new anti-tumor drugs is of great significance for improving patient treatment outcomes.

Chevalier, R. (2019). siRNA Targeting and Treatment of Gastrointestinal Diseases. Clin Transl Sci 12, 573-585.

Dekker, E., Tanis, P.J., Vleugels, J.L.A., Kasi, P.M., and Wallace, M.B. (2019). Colorectal cancer. Lancet 394, 1467-1480.

Dong, Y., Siegwart, D.J., and Anderson, D.G. (2019). Strategies, design, and chemistry in siRNA delivery systems. Adv Drug Deliv Rev 144, 133-147.

Gencer, A., Duraloglu, C., Ozbay, S., Ciftci, T.T., Yabanoglu-Ciftci, S., and Arica, B. (2021). Recent Advances in Treatment of Lung Cancer: Nanoparticle-based Drug and siRNA Delivery Systems. Curr Drug Deliv 18, 103-120.

Guo, Y., Zhu, Z., Huang, Z., Cui, L., Yu, W., Hong, W., Zhou, Z., Du, P., and Liu, C.Y. (2022). CK2-induced cooperation of HHEX with the YAP-TEAD4 complex promotes colorectal tumorigenesis. Nat Commun 13, 4995.

Heidel, J.D., Liu, J.Y., Yen, Y., Zhou, B., Heale, B.S., Rossi, J.J., Bartlett, D.W., and Davis, M.E. (2007). Potent siRNA inhibitors of ribonucleotide reductase subunit RRM2 reduce cell proliferation in vitro and in vivo. Clin Cancer Res 13, 2207-2215.

Kijima, S., Sasaki, T., Nagata, K., Utano, K., Lefor, A.T., and Sugimoto, H. (2014).

Preoperative evaluation of colorectal cancer using CT colonography, MRI, and PET/CT. World J Gastroenterol 20, 16964-16975.

Piawah, S., and Venook, A.P. (2019). Targeted therapy for colorectal cancer metastases: A review of current methods of molecularly targeted therapy and the use of tumor biomarkers in the treatment of metastatic colorectal cancer. Cancer 125, 4139-4147.

Song, J., Dang, X., Shen, X., Liu, Y., Gu, J., Peng, X., Huang, Z., Hong, W., Cui, L., and Liu, C.Y. (2023). The YAP-TEAD4 complex promotes tumor lymphangiogenesis by transcriptionally upregulating CCBE1 in colorectal cancer. J Biol Chem 299, 103012.