exam question, answer and references.
Hallmarks of cancer, how they lead to novel therapeutic development. 3 hallmarks discussed: limitless replicative potential, tissue invasion and metastasis and tumour-promoting inflammation.
Using appropriate examples, discuss how therapeutic targeting of the hallmarks of cancer has led
to the development of novel cancer therapeutics.
According to Hanahan and Weinberg (2011), in their updated review of the hallmarks of cancer
there are 10 distinct hallmark which are: self-sufficiency in growth signals, insensitivity to anti-
growth signals, tissue invasion and metastasis, limitless replicative potential, sustained angiogenesis,
evading apoptosis, avoiding immune destruction, tumour-promoting inflammation, genome
instability and mutation, deregulating cellular energetics. In this discussion 3 hallmarks will be
discussed and novel therapies which have been developed to target them.
limitless replicative potential
one of the biggest targets for cancer therapies is the control of the cell cycle. Cancer cells can
proliferate at an unprecedented rate with little regard for nutrient availability or growth signals. Otto
and Sicinski (2017) reviewed the current cell cycle targets and discussed how cyclin-dependant
kinases (CDKs) provided an efficient and specific target for anticancer therapies, that in some cases
CDK inhibition not only arrested the cell cycle but triggered tumour cell senescence or apoptosis,
whereas cell cycle proteins with check point functions had little impact on diminishing the cells’
ability to proliferate. Cyclin-dependent kinase inhibitors (CKIs) negatively regulate CDKs within the
cell cycle. Bury et al (2021) reviewed CDKs involvement in cancer and discussed recent studies that
have identified a third group of CKIs, ribosomal protein inhibiting CDKs (RPICs). Ribosomal proteins
are crucial in cell cycle control, but many have different roles regarding cancer, CX-5461 is an RNA-
polymerase I inhibitor currently being trialled. Yan et al (2021) conducted a study in which a
functional genomics screen was used to identify genes that when depleted will cooperate with CX-
5461 to inhibit homologous recombination (HR) - proficient high-grade serous ovarian carcinoma
(HGSC) cell proliferation. If CX-5461 is successful, the burden of chemoresistance in many types of
cancers would be severely diminished. Yan and colleagues concluded that not only can CX-5461 be
used to target HR-proficient HGSC but when combined with DNA topoisomerase I (TOP1) inhibitors it
can also be used to target HR-deficient HSGC, therefore CX-5461 and TOP1 inhibitors such as,
topotecan should be used in clinical trials to target 50% of HGSC patients who have HR-proficient
tumours and to patients with HR-deficient tumours.
Tissue invasion and metastasis
Metastasis of cancer cells results in various tumour formation and a poor clinical prognosis. Once a
cancer is spread throughout the body, any extra stress caused by surgery or chemotherapy can have
detrimental effects on the patients and increase tumour formation. Therefore, it is imperative to
prevent metastasise in early stages of cancer. Franses et al (2020) caried out a study into Pancreatic
ductal adenocarcinoma, one of the most common neoplastic diseases of the pancreas accounting for
more than 90% of all pancreatic cancers (Kleeff et al, 2016). Franses and colleagues investigated
circulating tumour cells (CTCs) to provide insight into novel therapeutic targets. They identified the
gene expression LIN28B to be a reliable biomarker for poor survival. They also discussed how
LIN28B, and lethal-7 microRNA (let-7 miRNA) interact to form a complex which provides a good
therapeutic target for inhibition to reduce metastasis, this shows a very promising target not only to
reduce metastasis in current cancer patients but possibly prevent reoccurrence in the future.
Tumour-promoting inflammation
Inflammation has been linked to carcinogenesis in two ways, firstly genetic events such as DNA
damage causing inflammation and neoplastic transformation, or inflammatory conditions which
promote carcinogenesis. Formylpeptide receptors (FPRs) are members of the chemoattractant G-
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