Anticancer agent – custirsen
Numerous mechanisms have been implicated in the development of resistance to cancer chemotherapies
Numerous mechanisms have been implicated in the development of resistance to cancer chemotherapies and progression of the disease. These include genes that prevent apoptosis and are controlled by heat shock factor protein.1 This protein has been implicated with cancer proliferation and survival, and thus its activity pathway represents an attractive target for drug intervention. Clusterin is one protein regulated by HSF-1, and it is expressed in numerous different human cancers, including prostate, colon, kidney, breast, lung and bladder. It acts as a cytoprotective chaperon, being activated after therapeutic stress, and is able to inhibit apoptosis, giving the cancer cells resistance to chemotherapy, hormone therapy and radiation therapy. When its expression is suppressed, the result is an increase in susceptibility to apoptotic death.
Canadian biotech OncoGeneX, in combination with Isis Pharmaceuticals of the US, is investigating the potential of antisense oligonucleotides to inhibit clusterin activity. These chemically modified lengths of single strand DNA are complementary to mRNA regions of the target genes, and they inhibit translation by forming RNA/DNA duplexes. It has to be accurately targeted to the target mRNA if it is to work. Custirsen sodium is one such antisense oligonucleotide, and is being investigated in clinical trials as a potential cancer therapy.1
Several Phase I and II trials have already been carried out in combination with other chemotherapy agents. For example, 85 patients with non-small cell lung cancer were given the drug in combination with gemcitabine and cisplatin chemotherapy, and there were 12 confirmed partial responses.2 It was also given to 15 patients with metastatic breast cancer in combination with docetaxel, in which five partial responses were seen, although this was just below the threshold for continuing the study.3
A randomised Phase II trial in 81 naïve patients with metastatic prostate cancer that was castration resistant were given either docetaxel (for a median of seven cycles) or docetaxel plus custirsen (median of nine cycles).4 The prostate specific antigen response rate of 50–60% was similar for both arms, but in the combination group no patients had a best PSA response of progression and just 4% had disease progression, while with docetaxel alone 7% had PSA progression, and 17% disease progression. Overall survival for the combination group was a median 23.8 months, and 16.9 for docetaxel alone. Phase III trials are now being planned.
References
1. Y. Saijo et al. Oncol. Res. 1994, 6, 243
2. J. Laskin et al. J. Clin. Oncol. 2007, 25 (18, Suppl.), Abst 7596
3. S. Chia et al. Clin. Cancer Res. 2009, 15, 708
4. K.N. Chi et al. J. Clin. Oncol. 2009, 27 (15, Suppl.), Abst 5012