Navigation Links
National Cancer Centre Singapore scientists discover p53 mutation hinders cancer treatment response

Reducing the level of mutant p53 gene increases susceptibility to treatment

Scientists from the National Cancer Centre Singapore (NCCS) have discovered the workings of the gene that has been hindering treatment response in cancer patients. This discovery was made after 5 years of studying the mutant form of the p53 gene, the major tumor suppressor in humans, which is generally found mutated in over 50% of all type of human cancers.

The dominant-negative (DN) effect of the mutant p53 gene in cancers was found to affect the outcome of cancer treatment modalities. DN effect is a phenomenon whereby one copy of mutant p53 that exists in cancer cells inhibits the tumor suppressor activity of the other wild-type p53 copy when they co-exist. The result is that a patient may either have poor response or earlier relapse of tumours after their treatment.

The research findings is significant in that it offers hope to improve cancer treatment outcomes by selectively inhibiting mutant p53's DN effect through several methods by generating selective and specific inhibitory molecules specific for some of the common hot-spot p53 point mutations. There are currently no drugs or compounds that can alleviate DN effects of mutant p53.

In order to understand the specific roles of mutant p53 DN properties in regulating acute treatment response and long-term tumourgenesis, a team of five researchers led by NCCS Prof Kanaga Sabapathy, the Principal Investigator in the Laboratory of Carcinogenesis and Head of the Division of Cellular & Molecular Research from NCCS, carried out experiments by generating genetically engineered knock-in mouse strains expressing varying levels of mutant p53. The results showed that DN effect is observed after acute p53 activation by a variety of chemotherapeutic drugs and irradiation, thereby affecting anti-cancer treatment. This breakthrough came after five years of intensive research.

It was found that mutant p53 have DN effects in a cell-type and dose-dependent manner, especially during acute p53 activation where p53 levels are elevated. Based on the above observations, efforts to generate specific inhibitors for the common hot spot p53 point mutations are underway. The inhibition of mutant p53 expression in cells carrying a wild-type and mutant p53 alleles can improve response to chemotherapeutic drugs.

In a further study, the researchers also questioned the possibility of the mutant p53 acquiring new functions (or Gain of Function) to drive carcinogenesis, transforming normal cells to cancerous cells. Their investigation comparing cells from genetically engineered mouse strains expressing 2 different types of p53 mutations: the R172H mutation versus the R246S mutation, which showed that Gain of Function (GOF) was found only in the former. This showed that GOF of mutated p53 is specifically dependent on mutation-type but not across all kinds of genetic mutations, highlighting diversity in properties of the different types of p53 mutations, thereby indicating that mutations found in human cancers can behave differently, and thus, need to be carefully assessed prior to treatment.

Thus, the existence of mutant p53 certainly has a negative impact on cancer treatment, whether it is through DN effect or GOF. Prof Sabapathy said that the team is now embarking on more research to determine the possibility of targeting mutant p53 without affecting wild-type p53 in human cells, paving way to clinical trials in the future to test the efficacy on cancer therapeutic response.

Contact: Rachel Tan

Related medicine news :

1. MU receives national award for using mind-body approach to improve health
2. International breast health global summit will focus on supportive care and quality of life
3. International conference to explore health of descendants of transatlantic slave trade
4. National poll: Low cost, lifesaving services missing from most older patients health care
5. UT MD Anderson President Ronald DePinho elected to National Academy of Sciences
6. Kessler Foundation researchers present at first International Congress on Cognition in MS
7. Dr. Yael Mosse will receive first Nachman Award in Pediatric Oncology at national conference
8. Georgetown physician leads national resveratrol study for Alzheimers disease
9. National initiative launched to change the way biology departments approach undergraduate education
10. Boston researcher, surgical oncologist receives national award
11. Internationally known expert in ovarian cancer to be honored at the ASCO Annual Meeting
Post Your Comments:
(Date:11/28/2015)... ... November 28, 2015 , ... Pixel Film Studios is ... panels to choose from, the possibilities are endless. Users have full control over angle ... ProPanel: Pulse masking effects, users are sure to get heads to turn. , ProPanel: ...
(Date:11/27/2015)... ... , ... The rapid speed at which Americans are aging ... is needed, especially with Alzheimer’s, dementia and other cognitive conditions becoming more prevalent. ... part of this equation: 80 percent of medical care occurs in the home, ...
(Date:11/27/2015)... ... November 27, 2015 , ... The print component ... Today in Atlanta, Dallas, New York, Minneapolis, South Florida, with a circulation of ... distributed nationally, through a vast social media strategy and across a network of ...
(Date:11/27/2015)... ... November 27, 2015 , ... A simply groundbreaking television series, "Voices in ... that delves into an array of issues that are presently affecting Americans. Dedicated to ... dialogue, this show is changing the subjects consumers focus on, one episode at a ...
(Date:11/27/2015)... ... November 27, 2015 , ... Dr. Thomas Dunlap ... Inc. and Dr. Tucker Bierbaum with Emergency Medicine at St., Joseph Health ... both STEMI and Sepsis conditions present in similar ways and require time-critical intervention to ...
Breaking Medicine News(10 mins):
(Date:11/25/2015)... 25, 2015 AAIPharma Services Corp./Cambridge Major ... at least $15.8  Million to expand its laboratories ... . The expansion will provide additional office ... growing demands of the pharmaceutical and biotechnology markets. ... will provide up to 40,000 square feet of ...
(Date:11/25/2015)... 25, 2015  Henry Schein, Inc., the world,s largest ... dental, medical and animal health practitioners, will unveil at ... Henry Schein ConnectDental® Pavilion , which brings together for ... solutions designed to help any practice or laboratory enter ... for a schedule of experts appearing at the Pavilion. ...
(Date:11/25/2015)... , Nov. 25, 2015  Trovagene, Inc. (NASDAQ: ... announced that Chief Executive Officer Antonius Schuh, Ph.D., is ... th Annual Piper Jaffray Healthcare Conference. ... New York Palace Hotel in New York ... p.m. EST. Mr. Schuh will be available for one-on-one ...
Breaking Medicine Technology: