Cancer
What is Cancer?
When the normal cell cycle mechanism is hampered either due to external factors or due to genetic abnormalities, uncontrolled cell growth occurs which restricts normal functioning of the respective organ. It can further spread to distant organs. Such phenomenon and associated disease conditions are categorized as ‘cancer’.
Why Cancer is a matter of concern?
Health problems due to cancer are increasing worldwide; according to global demographic characteristics, more than 20 million new cancer cases per year are expected by 20251. Fatality rate is also on the rise. Fatality in cancer majorly occurs due to spread and invasion of the tumor; thus, early stage diagnosis is crucial when tumor growth is localized in a limited region.
Which are current approaches (and their limitations) in treating cancer?
Anti-metastatic therapy is found to be most successful however it has limited clinical applications due to severe side effects3. Various events of metastasis have been targeted by numerous approaches such as, use of bisphosphonates in suppressing bone metastases has found to be effective but overall survival rate was unaltered3. Similarly, Avastin, an anti-VEGF monoclonal antibody, interferes with tumor angiogenesis but its application is limited due to acquired resistance leading to enhanced invasiveness 4, 5. Tumor invasion has been targeted by means of Integrin inhibitors (Abegrin, Vitaxin), MMP inhibitors, TGF-β inhibitors etc. however no success has been achieved at clinical trials3. Some of the molecules triggered tumor progression because of off-target activities 6, accompanied by severe intolerance via drug-drug interactions7. Imparting target specificity in therapeutic agents is an essential factor in anti-metastatic treatments8. Thus defining unique targets with key functions in cancer biology and further arresting their actions using small molecules with high selectivity is the solitary therapeutic approach in cancer treatments. Targeted therapy has proven to be an efficient alternative where molecular targets responsible for addictions, dependencies and vulnerabilities of cancer cells are identified and treated with either immunotherapy approach or with small molecular chemical entities 1, 9-11. Some of the successes in targeted therapy are as follows, inhibition of EGFR by gefitinib and erlotinib, inhibition of c-kit and PDGFR by imatinib, inhibition of VEGFR by sorafenib, inhibition of protein kinase ALK by crizotinib, and inhibition of BRAF by vemurafenib etc.1, 11. Targeting protein does face resistance issues, but if we target the associated DNA motif and control its transcription the resistances could be overcome.
Research in targeted cancer therapy is growing, here few among the huge pool of cancer targets
are listed for reference.
Various targets associated with cancer:
|
Target |
Function/family |
Associated cancer |
|
ACTB |
Cell cytoskeleton organization protein |
Low cancer specificity detected in all. |
|
ACTC1 |
Cell cytoskeleton organization protein |
Head and neck cancer, prostate cancer, testis cancer, urothelial cancer, glioma. |
|
CD151 |
Host platelet aggregation and keratinocyte migration in wound healing |
Prostate, skin squamous cell carcinoma, lung, colon, esophageal, pancreatic endometrial cancer. |
|
Claudin-2 |
Membrane protein, Tissue enhanced (brain, gallbladder, kidney, liver, seminal vesicle) |
Colorectal cancer, liver cancer, pancreatic cancer, renal cancer, stomach cancer. |
|
Hsp90aa1 |
Tumor-progression-protein chaperone |
Prostate cancer metastases to abdominal lymph nodes and liver |
|
miR-105 |
EV cargo, promotes metastasis |
Breast cancer |
|
MMP |
Matrix metallopeptidase family members are found as; secreted or expressed at the cell surface. May be involved in tumor invasion |
Metastatic breast, Prognostic marker in renal cancer and ovarian cancer. |
|
Nbeal2 |
Platelet-granule function |
Melanoma lung |
|
TGF-b |
Transforming growth factor, transcription factor-regulatory. |
Upregulated in tumor cells, and mutations in this gene. Prognostic marker in renal and head and neck cancers. |
|
KIAA0922 |
Putative transmembrane like protein, unknown function. |
Low cancer specificity. Prognostic marker in cervical cancer. |
|
KIF3B |
Kinesin motor complex subunit, vesicle transfer |
Melanoma, prostate, head and neck cancer |
|
KPNB1 |
Karyopherin Nuclear protein translocator |
GBM, prostate, cervical, B cell lymphoma, melanoma |
|
NR2F1 |
Orphan nuclear receptor, gene regulation |
Melanoma, ovarian, colon |
|
SRPK1 |
Kinase, splicing regulation |
Prostate, lung cancer |
|
MYC, KIT, KRAS, NRAS, HRAS, VEGF, BCL2 |
Various oncogenes found to be overexpressed in various cancer types. They are majorly involved in regulation of various stages of cell cycle. |
Melanoma, ovarian cancer, breast cancer, pancreatic cancer, etc. |
References:
1. J. Zugazagoitia, C. Guedes, S. Ponce, I. Ferrer, S. Molina-Pinelo and L. Paz-Ares, Clinical therapeutics, 2016, 38, 1551–1566.
2. D. Hanahan and R. A. Weinberg, Cell, 2000, 100, 57-70.
3. G. F. Weber, Cancer Lett., 2013, 328, 207-211.
4. F. Shojaei, Cancer Lett., 2012, 320, 130-137.
5. M. Ollero and D. Sahali, Nephrol. Dial. Transplant., 2015, 30, 1449-1455.
6. F. van Zijl, G. Krupitza and W. Mikulits, Mutat. Res., 2011, 728, 23-34.
7. K. Kessenbrock, V. Plaks and Z. Werb, Cell, 2010, 141, 52-67.
8. M. Iiizumi, W. Liu, S. K. Pai, E. Furuta and K. Watabe, Biochim. Biophys. Acta, 2008, 1786, 87-104.
9. C. Sawyers, Nature, 2004, 432, 294-297.
10. H. Neves and H. F. Kwok, BBA clinical, 2015, 3, 280-288.
11. S. Hoelder, P. A. Clarke and P. Workman, Molecular oncology, 2012, 6, 155-176.
12. K. Stolev, PH Beatty, JD Lewis, Expert review of anticancer therapy, 2020, 20-2 ,97-109.
Photo by National Cancer Institute on Unsplash
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