Featured Research

from universities, journals, and other organizations

Novel drug combination showed antitumor activity in patients with incurable BRCA-deficient cancers

Date:
April 7, 2013
Source:
American Association for Cancer Research (AACR)
Summary:
When given sequentially, two orally available experimental drugs -- sapacitabine and seliciclib -- worked together to elicit antitumor effects in patients with incurable BRCA-deficient cancers, according to phase I data.

When given sequentially, two orally available experimental drugs -- sapacitabine and seliciclib -- worked together to elicit antitumor effects in patients with incurable BRCA-deficient cancers, according to phase I data presented at the AACR Annual Meeting 2013, held in Washington, D.C., April 6-10. There are no drugs yet approved specifically for this patient population.

Related Articles


"Since we began to enroll predominantly patients who carried a BRCA mutation in the study, we have seen several responses among those patients, as well as instances of prolonged stable disease lasting more than a year," said Geoffrey Shapiro, M.D., Ph.D., associate professor of medicine at Dana-Farber Cancer Institute and Harvard Medical School in Boston, Mass.

Shapiro and colleagues initially designed the phase I study to exploit preclinical results that suggested that sapacitabine and seliciclib worked together synergistically. Sapacitabine is an oral nucleoside analogue that induces single-strand damage to DNA. If the damaged DNA is not repaired, it ultimately results in cell death. Repair of sapacitabine-induced DNA damage requires BRCA proteins, suggesting that BRCA-deficient cancers may be particularly sensitive.

Seliciclib inhibits cyclin-dependent kinases (CDKs); CDK inhibition has been shown to augment cancer cell death induced by drugs like sapacitabine by multiple mechanisms, in part by suppressing DNA repair pathways.

Researchers enrolled 38 patients with incurable solid tumors and adequate organ function. They assigned patients to treatment with sapacitabine twice daily for seven days followed by seliciclib twice daily for three days.

Four patients with BRCA-deficient pancreatic, breast or ovarian cancers had confirmed ongoing partial responses to the drug combination. Three patients are experiencing partial responses, with the longest lasting more than 78 weeks.

Furthermore, researchers observed stable disease of 12 weeks or more in eight additional patients, including two patients with ovarian and breast cancers who carried the BRCA mutation and whose stable disease lasted 64 weeks and 21 weeks, respectively.

The maximum tolerated doses were 50 mg sapacitabine twice daily and 1,200 mg seliciclib twice daily. Dose-limiting toxicities included reversible transaminase elevations and neutropenia. Adverse events were mild to moderate in intensity.

Results of skin biopsies after treatment showed a 2.3-fold increase in DNA damage induced by sapacitabine, as measured by gamma-H2AX immunohistochemistry. Additional DNA damage occurred after treatment with seliciclib with a 0.58-fold further increase in gamma-H2AX staining.

"Initially in the dose-escalation phase of the trial, this combination produced stable disease of modest duration in some patients, which has been the experience with sapacitabine and CDK inhibitors in solid tumors," Shapiro said. "However, other published research during the course of the study indicated the role of the homologous recombination pathway, dependent on BRCA proteins, for repair of sapacitabine-induced DNA damage. Additionally, the CDK proteins were implicated in DNA repair pathways. These findings prompted us to enroll patients with advanced cancer who had the BRCA mutation and led to the first partial responses and instances of durable stable disease."

Based on these emerging results, Shapiro and colleagues continue to enroll appropriate patients in the trial, where the combination has been most efficacious. Additional schedules of the combination therapy are under evaluation. According to Shapiro, if further work continues to confirm BRCA mutation status as a potential biomarker for response, these drugs, both individually and in combination, should ultimately be evaluated in larger groups of patients who carry BRCA mutation. If successful, these drugs may provide an important treatment alternative for patients with BRCA-deficient cancers.


Story Source:

The above story is based on materials provided by American Association for Cancer Research (AACR). Note: Materials may be edited for content and length.


Cite This Page:

American Association for Cancer Research (AACR). "Novel drug combination showed antitumor activity in patients with incurable BRCA-deficient cancers." ScienceDaily. ScienceDaily, 7 April 2013. <www.sciencedaily.com/releases/2013/04/130407183555.htm>.
American Association for Cancer Research (AACR). (2013, April 7). Novel drug combination showed antitumor activity in patients with incurable BRCA-deficient cancers. ScienceDaily. Retrieved October 30, 2014 from www.sciencedaily.com/releases/2013/04/130407183555.htm
American Association for Cancer Research (AACR). "Novel drug combination showed antitumor activity in patients with incurable BRCA-deficient cancers." ScienceDaily. www.sciencedaily.com/releases/2013/04/130407183555.htm (accessed October 30, 2014).

Share This



More Health & Medicine News

Thursday, October 30, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Mind-Controlled Prosthetic Arm Restores Amputee Dexterity

Mind-Controlled Prosthetic Arm Restores Amputee Dexterity

Reuters - Innovations Video Online (Oct. 29, 2014) A Swedish amputee who became the first person to ever receive a brain controlled prosthetic arm is able to manipulate and handle delicate objects with an unprecedented level of dexterity. The device is connected directly to his bone, nerves and muscles, giving him the ability to control it with his thoughts. Matthew Stock reports. Video provided by Reuters
Powered by NewsLook.com
Google To Use Nanoparticles, Wearables To Detect Disease

Google To Use Nanoparticles, Wearables To Detect Disease

Newsy (Oct. 29, 2014) Google X wants to improve modern medicine with nanoparticles and a wearable device. It's all an attempt to tackle disease detection and prevention. Video provided by Newsy
Powered by NewsLook.com
Can Drinking Milk Lead To Early Death?

Can Drinking Milk Lead To Early Death?

Newsy (Oct. 29, 2014) Researchers in Sweden released a study showing heavy milk drinkers face an increased mortality risk from a variety of causes. Video provided by Newsy
Powered by NewsLook.com
Obama: The US Will Not 'run and Hide' From Ebola

Obama: The US Will Not 'run and Hide' From Ebola

AP (Oct. 29, 2014) Surrounded by health care workers in the White House East Room, President Barack Obama said the U.S. will likely see additional Ebola cases in the weeks ahead. But he said the nation can't seal itself off in the fight against the disease. (Oct. 29) Video provided by AP
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:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

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