Medicosnext
Pancreatic cancer (PC), an aggressive malignancy with one of the highest mortality rates amongst cancers, is characterized by rapid development, fast growth, and frequent lymph node metastasis, which contribute to its very poor prognosis. The overall five-year survival rate of patients with pancreatic cancer is only about nine percent (American Cancer Society, https://urlzs.com/4MKJr). As there are no specific symptoms, pancreatic cancer is usually not detected at the early stages, and at the time of diagnosis, the tumor is confined to the pancreas in only about 10% of patients, with about 60% patients showing metastases. Treatment may include surgery, radiation, chemotherapy, or a combination of these three.
Radical surgery, the only possible way to cure the disease, can be conducted in only about 20% patients. In the advanced stage of pancreatic cancer, these treatments may not offer any benefit, and the doctor can only offer symptom relief (palliative care) to make the patient as comfortable as possible. Gemcitabine, which has been used in patients with PDAC for more than a decade, is the only first-line chemotherapeutic agent used for the palliative treatment of patients with PDAC.
Gemcitabine, along with radiation, work by causing damage to DNA; however, pancreatic cancer somehow repairs that damage, thus limiting these therapies’ effectiveness. Now, building on 20 years of research aimed at improving treatment of advanced pancreatic cancer, researchers from the Rogel Cancer Center at the University of Michigan have recently reported promising results of a phase 1 clinical trial of AZD1775, an inhibitor designed to block an enzyme called Wee1, which has a role in DNA damage repair. The researchers, led by Meredith Morgan, Ph.D., discovered that AZD1775 prevented pancreatic cancer from protecting itself against gemcitabine and radiation’s effects, while leaving normal cells comparatively unaffected.
Lead study author Kyle Cuneo, M.D., associate professor of radiation oncology at Michigan Medicine, opined that if the DNA damage response could be disabled in pancreatic cancer cells, it might eliminate resistance to treatment and sensitize the cancer to the effects of both radiation and chemotherapy. The trial was conducted on 34 patients with locally advanced pancreatic cancer, who were given AZD1775 along with radiation and gemcitabine, the objective being to find out the maximum dose of AZD1775 that could be tolerated in this combination. During the study, they observed that this combination led to better-than-expected overall survival.
Since pancreatic cancer is especially notorious for spreading to distant parts of the body, senior study author Ted Lawrence, M.D., Ph.D., Isadore Lampe Professor, and chair of radiation oncology at Michigan Medicine, stated, “If we’re ever going to cure pancreatic cancer, we’re going to need effective systemic treatment, as well as local therapy. Our data suggests that AZD1775 can do both.” The median overall survival in the study was 22 months, while a previous study using gemcitabine alone in a similar patient group observed overall survival of 12-14 months. Cuneo’s conclusion: “Adding AZD1775 to radiation and gemcitabine was relatively well tolerated with encouraging survival results. Further studies with this promising combination are needed.”
References:
1. ResearchGate, https://urlzs.com/yjHbG
2. Kyle C. Cuneo, Meredith A. Morgan, Vaibhav Sahai,QMatthew J. Schipper, Leslie A. Parsels, Joshua D. Parsels, Theresa Devasia, Mahmoud Al-Hawaray, Clifford S. Cho, Hari Nathan, Jonathan Maybaum, Mark M. Zalupski, Theodore S. Lawrence. Dose Escalation Trial of the Wee1 Inhibitor Adavosertib (AZD1775) in Combination With Gemcitabine and Radiation for Patients With Locally Advanced Pancreatic Cancer. Journal of Clinical Oncology, 2019; JCO.19.00730 DOI: 10.1200/JCO.19.00730
