Tag Archives: Symposium on Molecular Targets & Cancer Therapeutics

PARP Inhibitor MK-4827 Shows Anti-Tumor Activity in First Human Clinical Study

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MK-4827, a new drug that targets proteins responsible for helping cancer cells repair their damaged DNA, has shown promising anti-tumor activity in its first human clinical trial.

MK-4827, a new drug that targets proteins responsible for helping cancer cells repair their damaged DNA, has shown promising anti-tumour activity in its first human clinical trial. Some patients with a range of solid tumors, many of whom had been treated unsuccessfully for their cancer with other therapies, have seen their tumors shrink or stabilize for periods of between 46 days to more than a year. The research will be presented today (Thursday) at the 22nd EORTC–NCI–AACR [1] Symposium on Molecular Targets and Cancer Therapeutics, which is being held in Berlin, Germany.

PARP is a key signaling enzyme involved in triggering the repair of single-strand DNA damage. PARP inhibition has been demonstrated to selectively kill tumor cells lacking components of the homologous recombination (HR) DNA repair pathway while sparing normal cells. Known defects in HR repair include the well-characterized hereditary BRCA1 and BRCA2 mutations in breast and ovarian cancer, as well as nonhereditary BRCA mutations. (Photo Credit: AstraZeneca Oncology)

Laboratory studies of the drug, MK-4827, have shown that it inhibits proteins called PARP1 and PARP2 (poly(ADP)-ribose polymerase). PARP is involved in a number of cellular processes and one of its important functions is to assist in the repair of single-strand breaks in DNA. Notably, if one single-strand DNA break is replicated (replication occurs before cell division), then it results in a double-strand break.  By inhibiting the action of PARP, double-strand breaks occur, which in turn, lead to cell death. Tumors that are caused by a mutation in the BRCA1 or BRCA2 genes are susceptible to cell death through PARP inhibition because correctly functioning BRCA genes assist in repairing double-strand DNA breaks via a process called homologous-recombination-dependent DNA repair, whereas mutated versions are unable to perform this role. Normal cells do not replicate as often as cancer cells and they still have homologous repair operating; this enables them to survive the inhibition of PARP and makes PARP a good target for anti-cancer therapy.

In a Phase I trial [2] conducted at the H. Lee Moffitt Cancer Center (Tampa Florida, USA), University of Wisconsin-Madison (Madison, USA) and the Royal Marsden Hospital (London, UK), MK-4827 was given to 59 patients (46 women, 13 men) with a range of solid tumors such as non-small cell lung cancer (NSCLC), prostate cancer, sarcoma, melanoma and breast and ovarian cancers. Some patients had cancers caused by mutations in the BRCA1/2 genes, such as breast and ovarian cancer, but others had cancers that had arisen sporadically.

Robert M. Wenham, M.D., MS, FACOG, Clinical Director, Gynecologic Oncology, Department of Women's Oncology, H. Lee Moffitt Cancer Center

The drug was given in pill form once a day, and the researchers found that the maximum tolerated dose was 300 mg per day. Dr. Robert Wenham, Clinical Director for Gynecologic Oncology in the Department of Women’s Oncology at the Moffitt Cancer Center, who is presenting data on behalf of the participating investigators, said: “MK-4827 is generally well tolerated, with the main dose-limiting toxicity being thrombocytopenia – an abnormal decrease in the number of platelets in the circulatory blood. The most common side effects are mild nausea, vomiting, anorexia and fatigue.”

The researchers saw anti-tumor responses in both sporadic (non-inherited) and BRCA1/2 mutation-associated cancers [emphasis added]. Ten patients with breast and ovarian cancers had partial responses, with progression-free survival between 51-445 days, and seven of these patients are still responding to treatment. Four patients (two with ovarian cancer and two with NSCLC) had stable disease for between 130-353 days.

Dr. Wenham said: “Most patients in the trial had exhausted standard therapies and those who responded to this drug have benefited. Several patients have been receiving treatment for more than a year. The responses mean that MK-4827 is working as hoped and justify additional studies. Just how well MK-4827 works compared to other treatments is the goal of the next set of studies.”

He gave a possible explanation as to why patients with cancers that were not caused by BRCA1 or BRCA 2 gene mutations also responded to the PARP inhibition. “BRCA is a tumor suppressor gene that assists in repairing double stranded DNA breaks. In BRCA-mutation related cancers, loss of both copies of the gene results in a non-functional protein and thus BRCA deficiency. Because BRCA works with other proteins, BRCA-pathway related deficiency can be seen in the absence of two mutated copies of the BRCA genes. This may explain why responses have been reported for this class of drugs in non-BRCA mutant cancers.”

Dr. Wenham and his colleagues are recruiting more patients for additional studies and an expansion of the existing trial. “We want to understand what types of cancers will respond best to treatment with MK-4827,” he said. “Cohorts are currently open for patients with ovarian cancer, patients without germ-line BRCA mutations, and prostate cancer patients. Cohorts will open soon for patients with T-cell prolymphocytic leukemia, endometrial cancer, breast cancer and colorectal cancer. MK-4827 is also being studied in combination with conventional chemotherapy drugs.”

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References:

[1] EORTC [European Organisation for Research and Treatment of Cancer, NCI [National Cancer Institute], AACR [American Association for Cancer Research].

[2] This study was funded by Merck & Co., Inc. MK-4827 is owned by Merck & Co., Inc.

Dana-Farber Researchers “OncoMap” The Way To Personalized Treatment For Ovarian Cancer

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Researchers have shown that point mutations – mis-spellings in a single letter of genetic code – that drive the onset and growth of cancer cells can be detected successfully in advanced ovarian cancer using a technique called OncoMap. The finding opens the way for personalized medicine in which every patient could have their tumor screened, specific mutations identified, and the appropriate drug chosen to target the mutation and halt the growth of their cancer.

Researchers have shown that point mutations – mis-spellings in a single letter of genetic code – that drive the onset and growth of cancer cells can be detected successfully in advanced ovarian cancer using a technique called OncoMap. The finding opens the way for personalized medicine in which every patient could have their tumor screened, specific mutations identified, and the appropriate drug chosen to target the mutation and halt the growth of their cancer.

Using mass spectrometry for identifying the genetic make-up of cancer cells, OncoMap can determine the point mutations in tumors by utilizing a large panel of over 100 known cancer-causing genes (referred to as “oncogenes“). In the work to be presented today (Wednesday) at the 22nd EORTC–NCI–AACR [1] Symposium on Molecular Targets and Cancer Therapeutics in Berlin, researchers will describe how they used OncoMap to identify oncogene mutations in tumor samples obtained from women with advanced high-grade serous ovarian cancer. [2] Earlier in the year 76 mutations in 26 different genes had been found but, since then, further work in more tumor samples has found more.

Ursula A. Matulonis, M.D., Medical Director, Gynecologic Oncology, Dana-Farber Cancer Institute; Associate Professor, Medicine, Harvard Medical School

Dr. Ursula Matulonis, director/program leader in medical gynecologic oncology at the Dana-Farber Cancer Institute located in Boston, Massachusetts (USA) and Associate Professor of Medicine at Harvard Medical School, will tell the meeting:

“Epithelial ovarian cancer is the most lethal of all the gynecologic malignancies, and new treatments are needed for both newly diagnosed patients as well as patients with recurrent cancer. The success of conventional chemotherapy has reached a plateau, and new means of characterizing ovarian cancer so that treatment can be personalized are needed.

We know that many human cancers have point mutations in certain oncogenes, and that these mutations can cause cancer cells to have a dependence on just one overactive gene or signalling pathway for the cancer cell’s growth and survival – a phenomenon known as ‘oncogene addiction’. If the mutation that causes the oncogene addiction can be inhibited, then it seems that this often halts the cancer process. Examples of mutations that are successfully inhibited by targeted drugs are HER2 (for which trastuzumab [Herceptin®] is used in breast cancer), EGFR (erlotinib [Tarceva®] in lung cancer) and c-kit (imatinib [Gleevec®] in chronic myeloid leukemia). So if we know the status of specific genes in a tumor, then this enables us to choose specific treatments that are likely to work successfully against the cancer.”

Dr Matulonis and her colleagues used OncoMap to investigate the mutation status of high-grade serous ovarian tumors that were known not to be caused by inherited mutations in the BRCA 1 and BRCA 2 genes. They found mutations previously identified to be involved in ovarian cancer: KRAS, BRAF, CTNNB1 and PIK3CA. The KRAS and PIK3CA mutations were the most common, while BRAF was more rare. The researchers also identified a low frequency of mutations in many other different oncogenes.

Dr. Matulonis further noted:

“This study shows that it’s feasible to use OncoMap to identify whether a patient’s tumor has a mutation in an oncogene for which a known drug is available to target that specific gene, so as to enable us to place her on a clinical study of that drug; for instance, XL147 or GDC-0941 are inhibitors for the P13kinase mutation that are in clinical trials at present.  In addition, someone’s cancer could harbor a mutation (such as ALK) that is not known to be associated with ovarian cancer or has not yet been studied in ovarian cancer – these patients could be matched with a drug that inhibits that protein too. As new drugs get developed, this information would be used to match future drugs with patients and their cancers.”

The researchers hope that OncoMap will become a clinical test for all cancer patients at the Dana-Farber Cancer Institute before long, so that the genetic information obtained can be used to choose the best treatment for them.

Dr. Matulonis said:

“At present, only a few targeted therapies are being used for newly diagnosed ovarian cancer and most are being used to treat recurrent ovarian cancer, but this will change eventually. I have already referred several of our patients who are either newly diagnosed or have recurrent cancer and who have mutations (one with KRAS and one with PIK3CA) to our phase I program for drugs studies specific to these mutations.  For ovarian cancer, understanding mutational analysis is one piece of the genetic puzzle. Our group will also start looking for chromosomal and gene amplifications and deletions in patients’ tumors, which we know are important for ovarian cancer.”

Matulonis believes that OncoMap and other similar analytical tools will become mainstream practice in all cancer clinics before long. Tools for detecting genes with the incorrect numbers of copies or abnormal expression will also help doctors to choose the best treatment for individual patients.”

Source: Researchers map the way to personalised treatment for ovarian cancer, Abstract no: 35. Oral presentation in plenary session 2.  22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Berlin, Germany, November 16- 19, 2010.

References:

[1] EORTC [European Organisation for Research and Treatment of Cancer, NCI [National Cancer Institute], AACR [American Association for Cancer Research].

[2] The study was funded by the Madeline Franchi Ovarian Cancer Research Fund, twoAM Fund and the Sally Cooke Ovarian Cancer Research Fund.

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