Project description
Introduction to Colorectal cancer
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.
Figure 1 Age-standardised cancer incidence (A) and mortality (B) rates for countries in five continents
according to the latest WHO International Agency for Research on Cancer figures(Dekker et al., 2019)
Current State-of-the-Art for Colorectal cancer treatment
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.
The siRNA Delivery Systems
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.
Figure 2 Mechanism of RNA interference and strategies (Chevalier, 2019)
Our Project
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.
Figure 3 Mechanism of the siRNA treatment strategy
Reference
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
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