Nav: Home

'Epigenetic' drug may boost success of parp inhibitor treatment for leukemias and breast cancers

October 10, 2016

Drugs called PARP inhibitors, which sabotage cancer cells' ability to repair damage to their DNA, have shown some promise in treating human breast cancers that contain BRCA1 and BRCA2 gene mutations. Now, a new study in lab-grown cancer cells and mice suggests that their effectiveness could be strengthened and expanded to other forms of breast cancer and leukemia not linked to BRCA mutations by adding a so-called epigenetic drug.

A team of researchers at the Johns Hopkins Kimmel Cancer Center and the University of Maryland Greenebaum Comprehensive Cancer Center report that a combination of an experimental and not-yet-approved PARP inhibitor called talazoparib and an epigenetic drug called 5-azacytidine, approved for a pre-leukemic disorder called myelodysplasia, resulted in a strong antitumor response against breast cancer cells without BRCA mutations and in halting the growth of acute myeloid leukemia cells.

Between 25 and 28 days after the start of the combination treatment, human breast tumors grown in mice measured about half the volume of tumors treated with either drug alone, the team says.

In another set of experiments in which human leukemia cells were transplanted into mice, at 16 and 30 days after the start of the combination treatment, leukemia volumes in the mice were at least half as small as tumors treated with either drug alone.

The findings, described Oct. 10 in Cancer Cell, are the result of a collaboration between a team led by Stephen B. Baylin, M.D., co-director of the Cancer Biology Program at the Kimmel Cancer Center, and his wife, Feyruz V. Rassool, Ph.D., of the University of Maryland School of Medicine.

It was "somewhat of a surprise that leukemia cells were this sensitive to the combination treatment," says Baylin, "and if further research confirms our findings, it looks like it also could be useful for breast cancer and ovarian cancers for which PARP inhibitors have not been useful as yet."

PARP inhibitors work by blocking the poly (ADP-ribose) polymerase enzyme or PARP, which helps repair naturally occurring breaks in strands of DNA. Some cancers rely more frequently on PARP than others, Baylin says, and for tumors sensitive in that way, the inhibitors are one clinical weapon in sabotaging the cancer cells' ability to repair their own DNA.

Baylin adds that PARP inhibitors also "work according to how intensely and durably the PARP enzyme is trapped at certain DNA damage sites." Thus, he says, "If you can ramp up the duration and intensity of this trapping, you could potentially increase the efficacy of the drug."

The research team found that the combination of 5-azacytidine and talazoparib increased the time that PARP was trapped at sites of DNA damage in cancer cells, extending the time from 30 minutes to three to six hours after treatment.

Although talazoparib, which is being developed by Medivation Inc., is not yet approved by the Food and Drug Administration, another PARP inhibitor called olaparib is approved for patients with advanced ovarian cancer and BRCA mutations. Scientists are searching for ways to expand and improve the use and effectiveness of PARP inhibitors, Baylin says.

Epigenetic drugs work by changing the property of DNA -- how it's coiled and processed. Specifically, 5-azacytidine blocks proteins that attach gene-regulating methyl groups to DNA and traps those proteins on DNA. The proteins blocked by 5-azacytidine also interact with PARP enzymes at DNA damage sites, explains Baylin. "We figured that if we pair 5-azacytidine and a PARP inhibitor like talazoparib, we may be able to increase PARP trapping at DNA damage sites," says Baylin.

Baylin says plans to test the combination therapy in a clinical trial for patients with advanced acute myeloid leukemia are pending at the University of Maryland. "Advanced leukemia is a tough disease to treat, and we urgently want to give patients more options," Baylin says. "Hopefully, success in this trial will also spur subsequent clinical trials for other tumor types like breast cancer and ovarian cancer without BRCA mutations."
Baylin and Rassool are members of a Stand Up To Cancer team -- which Baylin co-leads with Peter Jones, Ph.D., at the Van Andel Research Institute -- which aims to develop epigenetic therapy for patients with cancer.

Other scientists who contributed to the research include Kimmel Cancer Center researchers Limin Xia and Yi Cai; Nidal E. Muvarak, Khadiza Chowdhury, Carine Robert, Pratik Nagaria, Søren M. Bentzen, Eun Yong Choi, Vu H. Duong, Maria R. Baer, Rena G. Lapidus, Ying Zou and Zeba N. Singh of the University of Maryland School of Medicine; Marina Bellani and Michael M. Seidman of the National Institute on Aging; and Tyler Rutherford of Stevenson University.

Robert, Rassool and Baylin share co-inventorship on U.S. Provisional Patent Application No. 61/929,680 for the concept of the combinatorial therapy.

Baylin and Rassool say they began this research after they were awarded a prize in 2012 from the Entertainment Industry Foundation and Stand Up To Cancer (SU2C), named for the late film producer Laura Ziskin, who died of breast cancer. Other funding was provided by the Van Andel-Research Institute-SU2C Epigenetics Dream Team, the Adelson Medical Research Foundation, Maryland Cigarette Restitution funds, the Leukemia Lymphoma Society and the National Institute on Aging (Z01 AG000746-08).

Johns Hopkins Medicine

Related Breast Cancer Articles:

Does MRI plus mammography improve detection of new breast cancer after breast conservation therapy?
A new article published by JAMA Oncology compares outcomes for combined mammography and MRI or ultrasonography screenings for new breast cancers in women who have previously undergone breast conservation surgery and radiotherapy for breast cancer initially diagnosed at 50 or younger.
Blood test offers improved breast cancer detection tool to reduce use of breast biopsy
A Clinical Breast Cancer study demonstrates Videssa Breast can inform better next steps after abnormal mammogram results and potentially reduce biopsies up to 67 percent.
Surgery to remove unaffected breast in early breast cancer increases
The proportion of women in the United States undergoing surgery for early-stage breast cancer who have preventive mastectomy to remove the unaffected breast increased significantly in recent years, particularly among younger women, and varied substantially across states.
Breast cancer patients with dense breast tissue more likely to develop contralateral disease
Breast cancer patients with dense breast tissue have almost a two-fold increased risk of developing disease in the contralateral breast, according to new research from The University of Texas MD Anderson Cancer.
Some early breast cancer patients benefit more from breast conservation than from mastectomy
Breast conserving therapy (BCT) is better than mastectomy for patients with some types of early breast cancer, according to results from the largest study to date, presented at ECC2017.
One-third of breast cancer patients not getting appropriate breast imaging follow-up exam
An annual mammogram is recommended after treatment for breast cancer, but nearly one-third of women diagnosed with breast cancer aren't receiving this follow-up exam, according to new findings presented at the 2016 Annual Clinical Congress of the American College of Surgeons.
Low breast density worsens prognosis in breast cancer
Even though dense breast tissue is a risk factor for breast cancer, very low mammographic breast density is associated with a worse prognosis in breast cancer patients.
Is breast conserving therapy or mastectomy better for early breast cancer?
Young women with early breast cancer face a difficult choice about whether to opt for a mastectomy or breast conserving therapy (BCT).
Breast density and outcomes of supplemental breast cancer screening
In a study appearing in the April 26 issue of JAMA, Elizabeth A.
Full dose radiotherapy to whole breast may not be needed in early breast cancer
Five years after breast-conserving surgery, radiotherapy focused around the tumor bed is as good at preventing recurrence as irradiating the whole breast, with fewer side effects, researchers from the UK have found in the large IMPORT LOW trial.

Related Breast Cancer Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Failure can feel lonely and final. But can we learn from failure, even reframe it, to feel more like a temporary setback? This hour, TED speakers on changing a crushing defeat into a stepping stone. Guests include entrepreneur Leticia Gasca, psychology professor Alison Ledgerwood, astronomer Phil Plait, former professional athlete Charly Haversat, and UPS training manager Jon Bowers.
Now Playing: Science for the People

#524 The Human Network
What does a network of humans look like and how does it work? How does information spread? How do decisions and opinions spread? What gets distorted as it moves through the network and why? This week we dig into the ins and outs of human networks with Matthew Jackson, Professor of Economics at Stanford University and author of the book "The Human Network: How Your Social Position Determines Your Power, Beliefs, and Behaviours".