Featured Research

from universities, journals, and other organizations

Herding cancer cells to their death

Date:
June 20, 2013
Source:
Ludwig Institute for Cancer Research
Summary:
Scientists have developed a therapeutic strategy that manipulates a mechanism driving cellular heterogeneity to treat advanced melanoma.

An advanced tumor is a complex ecosystem. Though derived from a single cell, it evolves as it grows until it contains several subspecies of cells that vary dramatically in their genetic traits and behaviors. This cellular heterogeneity is what makes advanced tumors so difficult to treat. Publishing their findings in today's online issue of Cancer Cell, an international team of scientists led jointly by Professors Colin Goding from the Ludwig Institute for Cancer Research who is based at the University of Oxford and José Neptuno Rodriguez-López from the University of Murcia, Spain describe a therapeutic strategy that manipulates a mechanism driving that heterogeneity to treat advanced melanoma. Their preclinical studies show that the strategy, which employs a new drug-like molecule in combination with an existing chemotherapy, is highly specific to melanoma cells and effective against tumors that resist all other therapies.

If caught early, melanoma is relatively easy to treat. But in its late stages, it is a stubborn and deadly cancer. Until about a decade ago, patients survived only about seven months after starting treatment. Since then, therapies, such as vemurafenib, that specifically target signaling proteins essential to the proliferation and survival of melanoma cells have extended the lives of some patients. But only about half respond to these targeted therapies, and even in those patients the cancer begins to resist the targeted therapy within six to nine months.

To bypass such resistance, the researchers developed a strategy that essentially pushes subtypes of melanoma cells that are not dividing -- and are therefore not susceptible to chemotherapy -- to become vulnerable to a shrewdly targeted drug.

To develop their therapy, the scientists first screened a variety of molecules to find one that boosts the expression of MITF, a master gene that, at high levels, pushes melanoma cells to proliferate and to express a protein known as Tyrosinase that fuels pigment production. The scientists found that methotrexate -- a drug currently used to treat autoimmune diseases and some other cancers, though not melanoma -- had precisely that effect. The Spanish team then synthesized a novel molecule called TMECG that is lethal only when it is chemically modified by Tyrosinase. When activated by Tyrosinase, TMECG disrupts the protein machinery of cell division and so poisons cells that are multiplying rapidly.

"The beauty of the therapy," says Professor José Neptuno Rodriguez-López, PhD, leader of the Spanish team at the University of Murcia, is that "TMECG is activated by a process that is specific to pigmented cells but not other cells. So, first the methotrexate sensitizes melanoma cells to the effects of TMECG. Then that molecule gets processed and activated by Tyrosinase to form an active compound that kills rapidly dividing cells. Even better, the methotrexate then delivers a second blow to melanoma cells by prompting them to commit suicide through a very specific mechanism."

The researchers found that the combined treatment efficiently destroyed melanoma cells in culture, even those derived from patient tumors resistant to vemurafenib and other targeted melanoma therapies. It also significantly suppressed tumors in one mouse model and diminished metastases in another.

In mice, the treatment combination does not appear to injure other pigmented cells, such as healthy cells of the skin, or those of the iris or the retina, probably because those cells are not rapidly proliferating. The researchers are now refining their new drug to improve its pharmacologic profile and figure out how to deliver it to the right places in the body.

"Think about what you ideally want from a cancer therapy," says Professor Colin Goding, PhD, Member of the Ludwig Institute for Cancer Research who is based at the University of Oxford. "You want a therapy that addresses cancer cell heterogeneity, that eradicates the tendency of cancer cells to become invasive, that works on cells that are resistant to other therapies and that targets only the cancer cells and not any others. I think we've ticked all those boxes."

"By inducing melanoma to differentiate using an old chemotherapy drug, Saez-Ayala and colleagues took advantage of a protein expressed at high levels as a consequence of that differentiation to turn a molecule they have designed into a prolific melanoma killer," said Antoni Ribas, MD, PhD, Professor of Medicine at the University of California Los Angeles and the Jonsson Comprehensive Cancer Center in Los Angeles. "Based on their preclinical data, I believe that this two-step approach may have promise for treating melanoma."

Still, Goding notes, cancer cells are so mutable that some melanoma cells will inevitably develop resistance to the novel therapy. So he expects that, aside from showing that the strategy works in patients, future research will have to show that it can be combined with other cancer therapies to get around such resistance. "That's how we should be thinking about cancer therapy," he says. "The complexity of the disease is such that any one therapy probably won't work on its own. But if you give complementary therapies that work in completely different ways, then I think you have a chance against this disease."

The work, supported also by scientists and clinicians from the Hospital Virgen de la Arrixaca in Murcia and the Churchill Hospital in Oxford, was funded by the Ludwig Institute for Cancer Research, Ministerio de Ciencia e Innovación; Fundación Séneca, Región de Murcia; and the Fundación de le Asociación Espanola contra el Cáncer (AECC).


Story Source:

The above story is based on materials provided by Ludwig Institute for Cancer Research. Note: Materials may be edited for content and length.


Journal Reference:

  1. Magalí Sáez-Ayala, María F. Montenegro, Luis Sánchez-del-Campo, María Piedad Fernández-Pérez, Soledad Chazarra, Rasmus Freter, Mark Middleton, Antonio Piñero-Madrona, Juan Cabezas-Herrera, Colin R. Goding, José Neptuno Rodríguez-López. Directed Phenotype Switching as an Effective Antimelanoma Strategy. Cancer Cell, 2013; DOI: 10.1016/j.ccr.2013.05.009

Cite This Page:

Ludwig Institute for Cancer Research. "Herding cancer cells to their death." ScienceDaily. ScienceDaily, 20 June 2013. <www.sciencedaily.com/releases/2013/06/130620132114.htm>.
Ludwig Institute for Cancer Research. (2013, June 20). Herding cancer cells to their death. ScienceDaily. Retrieved July 22, 2014 from www.sciencedaily.com/releases/2013/06/130620132114.htm
Ludwig Institute for Cancer Research. "Herding cancer cells to their death." ScienceDaily. www.sciencedaily.com/releases/2013/06/130620132114.htm (accessed July 22, 2014).

Share This




More Health & Medicine News

Tuesday, July 22, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Gilead's $1000-a-Pill Drug Could Cure Hep C in HIV-Positive People

Gilead's $1000-a-Pill Drug Could Cure Hep C in HIV-Positive People

TheStreet (July 21, 2014) — New research shows Gilead Science's drug Sovaldi helps in curing hepatitis C in those who suffer from HIV. In a medical study, the combination of Gilead's Hep C drug with anti-viral drug Ribavirin cured 76% of HIV-positive patients suffering from the most common hepatitis C strain. Hepatitis C and related complications have been a top cause of death in HIV-positive patients. Typical medication used to treat the disease, including interferon proteins, tended to react badly with HIV drugs. However, Sovaldi's %1,000-a-pill price tag could limit the number of patients able to access the treatment. TheStreet's Keris Lahiff reports from New York. Video provided by TheStreet
Powered by NewsLook.com
$23.6 Billion Awarded To Widow In Smoking Lawsuit

$23.6 Billion Awarded To Widow In Smoking Lawsuit

Newsy (July 20, 2014) — Cynthia Robinson claims R.J. Reynolds Tobacco Company hid the health and addiction risks of its products, leading to the death of her husband in 1996. Video provided by Newsy
Powered by NewsLook.com
Tooth Plaque Provides Insight Into Diets Of Ancient People

Tooth Plaque Provides Insight Into Diets Of Ancient People

Newsy (July 19, 2014) — Research on plaque from ancient teeth shows that our prehistoric ancestor's had a detailed understanding of plants long before developing agriculture. Video provided by Newsy
Powered by NewsLook.com
Contaminated Water Kills 3 Babies in South African Town

Contaminated Water Kills 3 Babies in South African Town

AFP (July 18, 2014) — Contaminated water in South Africa's northwestern town of Bloemhof kills three babies and hospitalises over 500 people. The incident highlights growing fears over water safety in South Africa. Duration: 02:22 Video provided by AFP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins