oncology-p53-based Cancer Therapy

1. A presentation
on
p53-based Cancer Therapy
Presented by
Shuhylul Hannan
Roll No: ASH2213Msc105M
Session: 2021-2022
Year-M1 Term-01
Department of Biotechnology & Genetic Engineering
Noakhali Science and Technology University, Noakhali-3814

2. Contents
 p53 and Apoptosis
 p53 gene: The Guardian of the genome
 Principle of p53-based Cancer Therapy
 Methods used for p53-based Cancer Therapy
 Summary
2

3. "p53 and Apoptosis: Guardians of Cellular
Integrity" 3
p53
 This is a tumor suppressor gene (its activity stops the formation of tumors)
 Located on 17p13, first discovered in 1979
 The p53 protein is the product of TP53 gene
 P-protein
 53- weight of the protein, 53 kDa
 Located in almost all normal tissues
 Unstable and degrades very quickly
Functions
 Regulation of Cell cycle
 DNA repair
 Apoptosis
Apoptosis
 A naturally occurring process
by which a cell is directed to
programmed cell death

4. p53 gene: The Guardian of the genome
The p53 pathways
4

5. p53-based Cancer Therapy:
Principle 5
Increased understanding of the p53 response to develop powerful
drug combinations for chemotherapy:
These combinations aim to
 Increase the selectivity and safety of chemotherapy
 Selectively protecting normal cells and tissues
 while only targeting cancer cells.

6. Methods used for p53-based Cancer Therapy 6
 Gene therapy using wild-type p53 delivered by adenovirus
vectors.
 Development of oncolytic viruses designed to replicate and kill
only p53 defective cells.
 Development of siRNA and antisense RNA's that activate p53 by
inhibiting the function of negative regulators Mdm2, and HPV E6.
 Development of p53-based vaccines that elicit T-cell and B-cell
responses to p53.
 Use of small molecules, such as p53 mdm2 interaction inhibitors,
to directly or indirectly activate the p53 response.

7. GENE THERAPY BASED APPROACHES 7
**Gene therapy using wild-type p53 delivered by adenovirus vectors**
This approach aims to
 Replace the mutated or inactive p53 gene with wild-type p53
genes
 Restoring the tumor-suppressive functions of p53 and
 Potentially leading to cancer cell death.
This therapy has been widely used in China and has shown promise in
treating p53-deficient cancer cells.

8. GENE THERAPY BASED APPROACHES 8

9. Use of small molecules, such as p53 mdm2
interaction inhibitors
9
Small molecules, including p53 mdm2 interaction inhibitors
 Blocking the interaction between p53 and Mdm2, a negative
regulator of p53, that activate the p53 response in cancer cells.
 Inhibiting proteins that deacetylate p53, kinase inhibitors,
molecules that block deubiquitinating enzymes, and molecules
that mobilize ribosomal proteins.
 It is a promising approach for cancer treatment, and
 Ongoing research needed to optimize their efficacy.

10. Targets for small molecules to activate the p53
response
10

11. Targets for small molecules to activate the p53
response
11

12. Cyclotherapy: a cancer treatment approach 12

13. Cyclotherapy 13
 Involves using two drugs in combination to selectively kill p53
mutant tumor cells.
 The first drug is a nongenotoxic p53 inducer, induces a
reversible cell cycle arrest in normal cells
 However, p53 mutant tumor cells continue to divide in the
presence of the drug.
 While the second drug is anti-S phase or antimitotic drug
which is designed to kill only proliferating cells.

14. Cyclotherapy 14
 Subsequent treatment with second drug, an anti-S phase or
antimitotic drug then kills the tumor cells but not the normal
cells.
 Following drug removal, only the normal cells survive and can
divide.
 This approach reduces side effects such as neutropenia, hair loss,
immune suppression, and mucositis
 Cyclcotherapy is still in the experimental stage and
requires further research and development before it can
be used in clinical practice.

15. Summary
 p53-based cancer therapy involves targeting the p53 tumor
suppressor protein, which is frequently mutated in human tumors.
 Different approaches are being explored for p53-based therapy,
including gene therapy using wild-type p53 delivered by adenovirus
vectors, small molecule drugs that restore p53 wild-type conformation
and activity.
 Other strategies include, manipulating p53 regulators, and activating
p53 effectors leading to tumor regression and elimination.
 Despite the extensive research and development in this field, p53-
based therapies have yet to fulfill their promise, but new insights into
combination therapies, microRNA regulation, clinical trial
structuring, and stem cell involvement may help optimize p53-based
15

16. References
1. David, P., Lane., Chit, Fang, Cheok., Sonia, Lain. (2010). p53-based Cancer Therapy.
Cold Spring Harbor Perspectives in Biology, doi: 10.1101/CSHPERSPECT.A001222
2. Tomasz, Stoklosa., Jakub, Golab. (2005). Prospects for p53-based cancer therapy.. Acta
Biochimica Polonica, doi: 10.18388/ABP.2005_3445
3. William, M., Gallagher., Robert, S., Brown. (1999). p53-Oriented cancer therapies:
Current progress. Annals of Oncology, doi: 10.1023/A:1008368500557
4. Klas, G., Wiman. (1998). New p53-based anti-cancer therapeutic strategies. Medical
Oncology, doi: 10.1007/BF02787204
5. Aime, A., Levesque., Alan, Eastman. (2007). p53-based cancer therapies: Is defective
p53 the Achilles heel of the tumor?. Carcinogenesis, doi: 10.1093/CARCIN/BGL214
6. Nasser, Pouladi., Roghayeh, Dehghan., Mohammad, Ali, Hosseinpour, Feizi., Sepehr,
Abdolahi., Masoumeh, Valipour. (2018). P53 researches and cancer therapy.
16

17. Thank You
for
Your Time & Attention.
Any question?

18. Development of p53-based vaccines that elicit
T-cell and B-cell responses to p53
18
**Development of p53-based vaccines that elicit T-cell and B-cell responses to p53:**
- p53-based vaccines are being developed to elicit T-cell and B-cell responses against p53,
which could potentially aid in eliminating cancer cells. These vaccines aim to stimulate the
immune system to recognize and target cancer cells that express p53.
- Clinical trials are underway to evaluate the efficacy of p53-based vaccines in activating
immune responses against p53. These vaccines are being tested in patients with various
types of cancers, including lung cancer, colorectal cancer, and ovarian cancer.
- The altered processing of p53 in tumor cells can trigger T-cell and B-cell responses to p53,
which may contribute to the elimination of cancer cells. The development of p53-based
vaccines is an active area of research, with the goal of harnessing the immune system's
ability to target and destroy cancer cells.

19. Development of siRNA and antisense RNA's
that activate p53
19
**Development of siRNA and antisense RNA's that activate p53 by inhibiting the function of
negative regulators Mdm2, MdmX, and HPV E6:**
- siRNA and antisense RNA molecules are being developed to activate p53 by inhibiting the
function of negative regulators such as Mdm2, MdmX, and HPV E6. These molecules target
the mRNA of these negative regulators, leading to their degradation or inhibition, which in
turn allows p53 to function properly.
- In the case of Mdm2, siRNA targeting Mdm2 has shown effectiveness in activating the p53
response in tumors where p53 is wild type but inactivated by Mdm2. This approach can be
highly effective in restoring p53 function and potentially inhibiting tumor growth.
- Similarly, siRNA targeting HPV E6, which binds to and targets p53 for inactivation, has been
shown to induce a rapid and effective p53 response in tumors associated with human
papilloma viruses. This strategy can help restore p53 function in these cancers.

20. Development of oncolytic viruses designed to
replicate and kill only p53 defective cells
20
**Development of oncolytic viruses designed to replicate and kill only p53 defective cells:**
- Oncolytic viruses are being developed to specifically target and kill cancer cells that have
defective p53 function. These viruses are designed to replicate within the cancer cells and
induce cell death, while sparing normal cells with intact p53 function.
- The goal of using oncolytic viruses is to exploit the vulnerability of p53-defective cancer
cells and selectively eliminate them, potentially leading to tumor regression.
- By selectively targeting p53-defective cells, oncolytic viruses offer a potential therapeutic
strategy for cancers with p53 mutations or inactivation.
- The development of oncolytic viruses as a treatment approach is an active area of
research, with the aim of improving their specificity, efficacy, and safety for clinical use.