Advanced soft tissue sarcomas respond to new drug GDC-0575 combined with gemcitabine

December 01, 2016

Munich, Germany: Researchers working to find effective treatments for soft tissue sarcomas have discovered that combining a new anti-cancer drug with an existing one kills cancer cells not only in the laboratory but also in the first two patients treated with it, leading to unusually long-lasting periods without the disease progressing.

Soft tissue sarcomas - cancers of soft tissues such as fat, muscles, blood vessels, nerves, tendons and ligaments - are rare but difficult to treat successfully if they are advanced and have spread to other parts of the body (metastasised).

In a late-breaking presentation at the 28th EORTC-NCI-AACR [1] Symposium on Molecular Targets and Cancer Therapeutics in Munich, Germany, today (Friday), Professor Antoine Italiano, head of the Early Phase Trials and Sarcoma Units at Institut Bergonié, Bordeaux, France, described how a new drug, GDC-0575, inhibits a molecule called Checkpoint kinase 1 (CHK1) that regulates the response of cancer cells to DNA damage. By inhibiting CHK1, the drug prevents tumour cells recovering from DNA damage and they die. Combining GDC-0575 with gemcitabine, a cancer-killing drug that is already used for treating sarcomas, proved remarkably effective.

"Soft tissue sarcomas represent a rare group of malignant tumours. Despite the use of surgery, radiotherapy and chemotherapy to treat the tumour in the localised region in which it started, up to 40% of patients will develop recurrence with cancer cells spreading to other parts of the body," he said. "The number of drugs approved to manage patients with advanced sarcoma is very low and patients in this setting have a very poor outcome with a median [average] overall survival of only 12-18 months. Gemcitabine is one of the drugs used in patients with advanced soft tissue sarcoma.

"We did this study in order to assess if combining a CHK1 inhibitor with gemcitabine can improve the anti-tumour efficacy in pre-clinical models of the disease. We observed a very strong synergy between the CHK1 inhibitor GDC-0575 and gemcitabine in sarcoma cells in the lab, but also in mice. The combination of the two drugs significantly reduced tumour growth rate in comparison to treatment with just one drug both in the lab and in the mice.

"Interestingly, two patients, who were treated with such a combination in a phase I clinical trial [3] had a meaningful response, which is quite unusual in this setting. Despite a significantly lower dose of gemcitabine than is used routinely, the tumours in these patients shrank rapidly and substantially for an unusually long-lasting time. The first patient who had a leiomyosarcoma [2] with extensive metastases in the peritoneum had a partial response, in which the tumour shrank, that lasted for one year. The second patient, who had lung metastases, had a complete response, in which the cancer completely disappeared, that is still ongoing nine months after the start of treatment."

The patients had been given 250mg/m3 a week of gemcitabine instead of the more usual 660 mg/m3. Gemcitabine was given intravenously and GDC-0575 was given orally with a range of different doses.

The researchers analysed tumour samples taken from the first patient at the start of treatment and when the cancer started to grow again to identify genes that might play a role in the patient's eventual resistance to the treatment. "We have identified 16 potential genes and these data now have to be validated by further studies," said Prof Italiano.

The study is no longer enrolling new patients but Prof Italiano said: "Based on these pre-clinical and preliminary clinical data we will try to set up a phase II clinical trial to assess the safety and efficacy of gemcitabine plus a CHK1 inhibitor in soft-tissue sarcoma."

Chair of the scientific committee for the Symposium, Professor Jean Charles Soria from the Institut Gustave Roussy (France), commented: "Exceptional responders in the clinical setting represent unique opportunities to better understand the biological basis underlying tumour shrinkage. This is very well exemplified in this work, where not only the basis of response is analysed by sequencing all the active genes in the tumour samples, but also the basis of acquired secondary resistance."
-end-
[1] EORTC [European Organisation for Research and Treatment of Cancer, NCI [National Cancer Institute], AACR [American Association for Cancer Research].

[2] Leiomyosarcoma is one of the more common types of soft tissue sarcomas to develop in adults.

[3] Clinical trial no: NCT01564251. "A study of GDC-0575 alone and in combination with gemcitabine in patients with refractory solid tumours or lymphoma".

ECCO-the European CanCer Organisation

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.