Tortoise and the Hare: New Drug Stops Rushing Cancer Cells, Slow and Steady Healthy Cells Unharmed
ScienceDaily (Mar. 2, 2012)
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Instead of going with the flow of the natural cell cycle, cancer cells amplify two signals -- PLK1 and PI3K -- which allows them to blast through the cell cycle and divide much more quickly. In the process, they break this step of the natural cell cycle, known as the G1 regulatory mechanism, and thus depend on the kick of PLK1 and P13K to push at a frenzied pace through replication.
It's specifically these two signals, PLK1 and PI3K, that rigosertib targets. With these signals turned off, cancer cells get stuck and die in the stage of the cell cycle called M phase -- while healthy cells that stuck to the slower, natural method of division chug past unharmed.
"This one-two punch, targeting these two distinct signaling pathways, allows us to interfere twice with cancer cells' ability to replicate," Messersmith says. And it also allows doctors to target cancers that may have evolved resistance to one or the other target.
The phase I trial established the safe dosage as 2-hour infusions on days 1, 4, 8, 11, 15 and 18 of 1800 mg/m2 when combined with gemcitabine 1000 mg/m2 on days 1, 8 and 15, administered in 28-day cycles. Now the promising therapy has moved into a phase II/III trial in metastatic pancreas cancer to more precisely test its effectiveness (NCT01360853 on clinicaltrials.gov) .
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Clin Cancer Res. 2012 Feb 14. [Epub ahead of print]
Phase 1 study of rigosertib, an inhibitor of the phosphatidylinositol 3-kinase and polo-like kinase 1 pathways, combined with gemcitabine in patients with solid tumors and pancreatic cancer.
Ma WW,
Messersmith WA,
Dy GK,
Weekes CD,
Whitworth A,
Ren C,
Maniar M,
Wilhem F,
Eckhardt SG,
Adjeii AA,
Jimeno A.
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Source
Medicine, Roswell Park Cancer Institute.
Abstract
PURPOSE:
Rigosertib (R), a dual non-ATP inhibitor of polo-like kinase and phosphatidylinositol 3-kinase pathways, and gemcitabine (G) have synergistic anti-tumor activity when combined in preclinical studies. This phase 1 study aimed to determine the recommended phase 2 dose (RPTD) of the combination of rigosertib and gemcitabine in cancer patients.
Methods: Patients with solid tumors who failed standard therapy or were candidates for gemcitabine-based therapy were eligible. Gemcitabine was administered on days 1, 8 and 15 on a 28-day cycle; rigosertib on days 1, 4, 8, 11, 15 and 18. Pharmacokinetic studies were performed during an expansion cohort of advanced pancreatic ductal adenocarcinoma (PDA) patients.
RESULTS:
Forty patients were treated, 19 in the dose escalation phase and 21 in the expansion cohort. Dose levels evaluated were (G/R mg/m2): 750/600 (n=4), 750/1200 (3), 1000/600 (3), 1000/1200 (3) and 1000/1800 (6+21). One dose limiting toxicity (death) occurred at the highest dose level (1000/1800) tested. Non-dose limiting ≥grade 2-3 toxicities included neutropenia, lymphopenia, thrombocytopenia, fatigue, and nausea. Grade 3/4 neutropenia, thrombocytopenia and fatigue were seen in 2, 1, and 2 patients in the expansion cohort. Partial responses were observed in PDA, thymic cancer and Hodgkin's lymphoma, including gemcitabine-pretreated PDA. Rigosertib's pharmacokinetic profile was not affected by gemcitabine.
CONCLUSION:
The RPTD established in this study is rigosertib 1800 mg/m2 and gemcitabine 1000 mg/m2. This regimen is well tolerated with a toxicity profile of the combination similar to the profile of gemcitabine alone. Antitumor efficacy was observed in patients who previously progressed on gemcitabine-based therapy.
- PMID:
- 22338014
- [PubMed - as supplied by publisher]
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