Anti-Cancer Targeted Therapy

“In a recent study, about 70 percent of all ovarian cancer patients are found at a very advance stages (3 or 4), and of those woman, about 80 percent will recur.6 As a result, ovarian cancer recurrence is something that most women fear. Before Zejula was approved, the treatment for cancer recurrence was chemotherapy.7 One of the primary goals to treat recurrent diseases is to subside or prevent symptoms of the disease while keeping the side effects to a minimum. The treatment for women with recurrent disease is normally founded on the time since her last treatment utilizing a platinum chemotherapy drug.7,11 Zejula is a maintenance orphan drug used to treat patients with recurrent ovarian, fallopian tube or primary peritoneal (type of cancer in the abdomen) cancer.

Lead Identification & SAR Profile

Targeted therapy is tied in with distinguishing highlights of cancer cells. This data is used to make a targeted therapy to attack the cancer cells without harming the normal cells, in this manner prompting fewer side effects. Each type of targeted therapy works fairly differently, but all interfere with the ability of the cancer cell to grow, divide, fix and/or communicate with other cells. The molecular target name of Zejula is Niraparib, an anti-cancer targeted therapy. Niraparib is a poly ADP-ribose polymerase (PARP) enzyme inhibitor highly selective for PARP1 and PARP2. PARP1 and PARP2 are involved in detecting DNA damage and promote repairs. Inhibiting PARP1 and PARP2 enzymatic activity results in DNA damage, apoptosis, and cell death. Niraparib instigates cytotoxicity in tumor cell lines with and without BRCA1/2 deficiencies. 1,3,12 PARP, inhibitors hinder an enzyme in repairing harmed DNA. By hindering the enzyme, DNA inside cancer cells may be less inclined to be fixed, prompting cell death and conceivably slowing down or stopping tumor growth.12 The BRCA genes (BRCA1 and BRCA2) are normally in DNA repair, and a mutation in these genes interferes with this pathway function. PARP inhibitors make it troublesome for cells that generally have a BRCA mutation to grow and divide. Researchers are further testing to see if PARP inhibitors can keep the cancer from returning after chemotherapy.

The dosing is 300 mg (three 100 mg capsules) orally that can be taken at any time of day, with or without food. It is preferred to take at bedtime to help handle nausea or vomiting. Niraparib is not commonly given with the goal of cure, but is given to keep ovarian cancer from coming back if you are in remission; to stop to from developing or spreading.

Following oral administration of niraparib, peak plasma concentration, Cmax, is reached within 3 hours.4 The potency of Niraparib is PARP1 IC50 = 3.8nM and PARP2 IC50 = 2.1 nM.4 The mean of both the Cmax and AUC increased in a dose proportional manner over a range of 30 mg to 400 mg. Absolute bioavailability (F) is approximately 73%.11 Administration with a high fat meal (800 to 1,000 calories with approximately 50% of caloric content from fat) did not significantly impact the pharmacokinetics of niraparib.15 Thus far, the only obstruction mechanism that has been found in human tumors is hereditary reversion that corrects or bypasses the original BRCA1- or BRCA2-inactivating mutation.10 Although, some research from the fundamental and preclinical research suggest that resistance to PARP inhibitors may be induced by additional mechanisms involving hypomorphic activity of mutant BRCA1 alleles, upregulation of drug efflux pumps, and rewiring of the DNA damage response. Niraparib aims for the carboxylesterase enzyme. Preclinical models will be instrumental to develop techniques for adequate patient stratification, as well as treatment strategies that avert or counteract resistance to PARP inhibitors.8,13″

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