Experimental drug guadecitabine found safe in patients with colorectal cancer: Combination with standard chemotherapy shows promise in overcoming treatment resistance

In continuation of my update on guadecitabine (SGI-110)

In a small, phase I clinical trial, Johns Hopkins Kimmel Cancer Center researchers say they show for the first time that the experimental drug guadecitabine (SGI-110) is safe in combination with the chemotherapy drug irinotecan and may overcome resistance to irinotecan in patients with metastatic colorectal cancer. Results of the study are expected to be presented April 17 at the American Association for Cancer Research (AACR) Annual Meeting 2016 in New Orleans (abstract CT017).

Guadecitabine works to reverse a so-called epigenetic change in cancer cells known as methylation, which may alter genetic activity in cells in a way that can block the action of tumor-suppressing genes, pushing cells to become cancerous and resistant to therapy. By reversing this change in cancer cells, the drug restores cancer cells' vulnerability to drugs such as irinotecan.

The clinical trial included 22 patients with metastatic colorectal cancer who had been treated previously with irinotecan and whose disease was progressing. The patients were divided into four groups, each receiving different doses of guadecitabine in combination with irinotecan, over an average period of four months.

During the study, 15 patients had at least one imaging scan to retest the extent and location of their cancers -- with 12 patients experiencing stable disease -- for more than the four-month period, on average, and one patient experiencing a partial response to the treatment (measured as at least a 30 percent reduction in the size of the tumors.)

Although the study's main purpose was to test the safety rather than the effectiveness of guadecitabine doses, "we were very happy to see some patients who benefited from the combination of the therapies for many months to more than a year," says Nilofer Azad, M.D., professor of oncology at the Johns Hopkins University School of Medicine.

The study also showed signs that guadecitabine reduced methylation among the cancer cells. "We did see that giving a higher dose of the drug seemed to produce a better methylation response among patients," says Valerie Lee, M.D., a fellow at the Johns Hopkins Kimmel Cancer Center. "However, it seemed that patients were responding at all levels of the drug."

Among the side effects of the combined treatment, 16 patients experienced neutropenia, a low count of the infection-fighting white blood cells called neutrophils; five patients with neutropenia had fevers; three patients became anemic; and two patients developed thrombocytopenia, a lowered count of blood-clotting platelets. Other side effects included diarrhea (three patients), fatigue (two patients) and dehydration (two patients). There was one death during the study, possibly resulting from febrile neutropenia caused by the treatment.

The current study was based on previous studies in the laboratory of Nita Ahuja, M.D., director of the Sarcoma and Peritoneal Surface Malignancy Program and professor of surgery at the Johns Hopkins University School of Medicine, which showed that guadecitabine limited the growth of colorectal cancer cell lines when combined with irinotecan, says Azad.

The drug combination is being tested in an ongoing phase II clinical trial (NCT01896856) in a larger group of metastatic colorectal cancer patients at multiple institutions to determine the effectiveness of the dual therapy compared with chemotherapy regimens that do not include guadecitabine, says Azad.

Scientists leading the new study will also look for biomarkers in patients that could help determine which of them are most likely to benefit from guadecitabine and irinotecan. Lee says the research team will measure the amount of methylation in patients' cells when they begin their treatment and the presence of genes associated with irinotecan resistance, among other possible biomarkers.

In 2015, there were more than 130,000 people in the U.S. diagnosed with colon cancers. Five-year survival rates among people with localized colon cancers are more than 90 percent, but they are only 20 percent in those with metastatic cancer.

Guadecitabine is an experimental drug that has not been approved for use by the U.S. Food and Drug Administration. It is manufactured by Astex Pharmaceuticals, a supporter of the Johns Hopkins-led study. The research was also supported by the Van Andel Research Institute SU2C/AACR Epigenetics Dream Team.

Other scientists who contributed to the research include Judy Wang, Anup Sharma, Zachary Kerner, Stephen Baylin, Ellen Lilly, and Thomas Brown from Johns Hopkins; Anthony El Khoueiry from the University of Southern California; Henk Verheul and Elske Gootjes from Vrije Universiteit in the Netherlands; and Peter Jones from the Van Andel Research Institute.

Experimental drug guadecitabine found safe in patients with colorectal cancer: Combination with standard chemotherapy shows promise in overcoming treatment resistance 

Drug used for blood cancers may stop spread of breast cancer cells

In continuation of my update on Decitabine

A drug used to treat blood cancers may also stop the spread of invasive breast cancer, researchers at Mayo Clinic in Florida have discovered. Their study, published online in Breast Cancer Research, found that in the lab and in animals, the drug decitabine turns on a gene coding for protein kinase D1 (PRKD1) that halts the ability of cancer cells to separate from a tumor and spread to distant organs.

Drug used for blood cancers may stop spread of breast cancer cells

Ref : http://breast-cancer-research.com/content/15/2/R66

Cyclacel Presents New Phase 2 Data of Sapacitabine for MDS

We know that, Sapacitabine is an oral nucleoside analog prodrug that acts through a dual mechanism. The compound interferes with DNA synthesis by causing single-strand DNA breaks and induces arrest of the cell division cycle at G2 phase. Both sapacitabine and its major metabolite, CNDAC, have demonstrated potent anti-tumor activity in both blood and solid tumors in preclinical studies. In a liver metastatic mouse model, sapacitabine was shown to be superior to gemcitabine (Gemzar; Lilly) or 5-FU, two widely used nucleoside analogs, in delaying the onset and growth of liver metastasis.

Cyclacel has initiated a number of clinical trials to evaluate sapacitabine in both solid and hematological tumors laying the foundation for future Phase 2 studies and combination studies with other anti-cancer agents. Three Phase 1 studies have been completed, which evaluated safety and pharmacokinetics of a variety of dosing schedules in approximately 120 patients with solid tumors. Sapacitabine is currently being evaluated in two Phase 2 trials in patients with advanced cutaneous T-cell lymphoma (CTCL) and in elderly patients with acute myeloid leukemias (AML).

Now Cyclacel Pharmaceuticals, Inc. announced new data from an ongoing, multicenter, Phase 2 randomized trial of oral sapacitabine capsules in older patients with myelodysplastic syndromes (MDS) after treatment failure of front-line hypomethylating agents, such as azacitidine or decitabine.

Positive results from combination drug trial for late-stage ovarian cancer

In continuation of my update on  carboplatin

Researchers from IU Medical Sciences Program-Bloomington  and Indiana University Melvin, have found that, an experimental two-drug combination (decitabine & carboplatin) for treating late-stage ovarian cancer continues to produce strong results, leading its Indiana University researchers to actively pursue the next step, conducting a larger clinical trial to test the therapy and to see how it compares with existing treatments for ovarian cancer.

The researchers have been investigating the addition of decitabine, which is marketed as Dacogen in the United States, because they suspect it reactivates tumor suppression genes that are turned off in ovarian cancer cells and improves cells' susceptibility to anti-cancer drugs like carboplatin.

"The science associated with the trial is novel and exciting and could have impact in the future," she said.....

More...

Researchers Identify Two FDA Approved Drugs (Decitabine and Gemcitabine) That May Fight HIV....

Researchers at the University of Minnesota Academic Health Center have identified two drugs (Decitabine and Gemcitabine see structures)  that when combined, may serve as an effective treatment for HIV.

The researchers found that, two drugs, decitabine (left) and gemcitabine (below) (both FDA approved and currently used in pre-cancer and cancer therapy) were found to eliminate HIV infection in the mouse model by causing the virus to mutate itself to death an outcome researchers dubbed "lethal mutagenesis." Interestingly, this is for the first time that, this novel approach has been used to attack the deadly virus without causing toxic side effects. As the drugs are already approved for other purpose, it will be much easier to expedite the development of the drugs for human use.

"The findings provide hope that such an approach will someday help the 33 million people worldwide who currently live with HIV," Mansky said.

HIV mutates and evolves quickly. Rather than inhibiting virus growth and replication like current HIV drugs, this new drug combination forces the virus to do just the opposite evolve beyond control, to the point of extinction.

The lead researcher claims that HIV's ability to mutate makes it difficult to target and treat, and they wanted to take advantage of this behavior by stimulating HIV's mutation rate, essentially using the virus as a weapon against itself.

Researchers found that the drug concentrations needed to eliminate HIV infection cause no measureable cell toxicity and were effective against HIV cultures at concentrations well below the current levels used for cancer treatment.

Gemcitabine and decitabine have been administered in pre-clinical trials with mice. Initial findings confirm that the drugs are an effective antiviral therapy for HIV. And now the researchers are now in the process of modifying the drugs to forms that can be absorbed by the human body when taken orally.

Ref : http://jvi.asm.org/cgi/content/abstract/84/18/9301

Two-drug phase I trial shows promise in treating late-stage ovarian cancer

In continuation of my update on carboplatin .....

Researchers from Indiana University School of Medicine, have come up  with interesting finding from a two-Drug Phase I Trial Show, i.e.,  the combination of decitabine (see structure) and carboplatin appears to improve the outcome of women who have late-stage ovarian cancer. Researchers report four of 10 patients who participated in a phase I clinical trial had no disease progression after six months of treatment. One patient experienced complete resolution of tumor tissue for a period of time.

"Carboplatin is the most efficient drug therapy for ovarian cancer,"  unfortunately, patients with recurrent disease become resistant to the drug after one or two rounds claims the lead researcher.."

Decitabine was first used to treat the study patients intravenously daily for five days followed on the eighth day with carboplatin. After a month, the regimen begins again.

Encouraged by the results of the phase I trial, which determined the safety of two different dosing regimens, a phase II trial is now under way with 17 patients already enrolled. Phase II trials are primarily focused on assessing the effectiveness of a drug or treatment protocol.

As per the claim by the researcher, decitabine  (a known methylation inhibitor) can help return tumor suppression genes to an active state, and also improve cells' susceptibility to anti-cancer drugs like carboplatin. Researchers adds that decitabine isn't just targeting active ovarian cancer cells, but also cancer stem cells that seem to survive the first treatments. 

Researchers conclude that, by keeping tumor suppression genes from being methylated, carboplatin and other platinum-based treatments for ovarian cancer have a better chance of success in the late stages.

Ref : http://www3.interscience.wiley.com/journal/123500856/abstract?CRETRY=1&SRETRY=0