Each year, thousands of compounds are screened for possible anticancer properties.
Each year, thousands of compounds are screened for possible anticancer properties. From this vast pool, a few show promise and even fewer reach development for clinical applications. The road from drug discovery and design to clinical implementation is often 10-15 years. The evaluation of novel drugs has more recently moved to proof-of-concept and "go/no-go" strategic decision-making by pharmaceutical companies based on studies in tumor-bearing dogs. This talk will review some ongoing drug trials for chemotherapy agents currently under investigation.
Satraplatin (JM216) is the first orally bioavailable platinum anticancer chemotherapeutic. Platinum agents are effective in the treatment of many cancers and are widely used in the treatment of various carcinomas as well as osteosarcoma. In addition to the oral formulation, it is unique as compared to other platinum agents in that it causes less neuro- and nephrotoxicity. The dose-limiting toxicity seen in people and rodents to date is myelosuppression with lowest neutrophil and platelet counts both occurring at 2-4 weeks. Other side effects include nausea and diarrhea in approximately one third of patients. Pharmacokinetics and physical properties are known. The drug is very lipophilic and tends to build in tissues, maintaining detectable levels for up to 2 weeks after cessation of therapy. Satraplatin creates bulkier adducts than its platinum counterparts which may interfere with DNA repair, thus potentiating the damage. As a platinum-IV compound an additional step must occur to convert to a platinum-II compound for biologic activity. This affords improved longevity in the body and increases the chances that the active form will reach the target tissue. The ideal dosing scheme has been determined in rats to be daily for 5 days repeated every 3-5 weeks. This has been used in people in phase I/II studies. Decrease in tumor size has been seen in people with ovarian cancer, among others, and some studies report palliation of tumor-related pain even in the absence of objective tumor response. Satraplatin is currently in phase III trials for hormone-refractory prostate cancer but has not been evaluated in the adjuvant setting in people.
At the University of Missouri, we have recently completed a phase I/II study evaluating satraplatin in dogs with spontaneously-occurring tumors. We were able to determine the maximally tolerated dosage to be 30-35 mg/m2/d for 5 days, repeated every 3-4 weeks. The dose limiting toxicity was myelosuppression, almost always neutropenia. Of note, it was interesting that platelets almost always reached nadir before the neutrophils at days 10 and 14, respectively. Gastrointestinal side effects were mild, and no neurologic or renal side effects were noted. Preliminary data on outcome is promising with prolonged disease-free intervals for dogs treated in the adjuvant setting.
Oral chemotherapy agents offer many advantages for treatment of dogs with osteosarcoma. Satraplatin, once FDA approved, could be given in remote locations where it is not practical to oversee intravenous therapy. Time-consuming fluid diuresis will be avoided because of the lack of nephrotoxicity. Oral chemotherapy offers ease of administration and owners are able to deliver chemotherapy without the need for a hospital stay. In addition, the lack of repeated intravenous chemotherapy will spare peripheral veins.
Currently at the University of Missouri, we are evaluating satraplatin as a metronomic chemotherapy drug. The oral formulation and alkylating properties make this drug well-suited to metronomic therapy (frequent, regular chemotherapy dosing for antiangiogenic effects). Additionally, satraplatin has been shown in vitro to inhibit the proangiogenic signal stat3. To date, the drug has been well-tolerated though some myelosuppression has been seen.
Anthracycline antitumor antibiotics are broad-spectrum anticancer agents. Doxorubicin is the most widely known and widely used drug in this category. Elsamitrucin is a synthetic derivative within this group of drugs that has shown promise in human non-Hodgkin's lymphoma. Elsamitrucin is the most potent inhibitor of topoisomerase II known, and is unique in that it does not appear to be cardiotoxic and does not cause neutropenia. This latter characteristic suggests potential applications in combination chemotherapy protocols. Additionally, this drug can theoretically be administered more frequently than other drugs in this class. At the University of Missouri, we undertook a prospective phase 1 study in collaboration with the Veterinary Cancer Group of Southern California. Therapy was generally well-tolerated and a dosage of 0.08 mg/kg was identified for phase 2 trials.
SPI-1620, (N-Suc-[Glu9, Ala11,15] ET-1(8-21)) is a synthetic peptide analogue of endothelin-1 and a highly selective agonist of endothelin B receptor. Endothelin-1 acts upon endothelin (ET) receptors causing ET-B receptors in the endothelium to mediate vasodilation, and ET-A receptors in the pericytes to mediate vasoconstriction. Since pericytes are poorly organized or absent in most tumor vasculature, the net effect of a highly selective ET-B agonist is vasodilation in the tumor without concomitant alterations in vascular tone in normal tissues (normal pericytes can support blood vessels in normal tissue against the effects of ET-B stimulation). SPI-1620 can transiently enhance blood flow to tumors in rodent models, thus increasing accumulation of chemotherapeutic agents in tumor (but not normal) tissues, with improved efficacy.
At the University of Missouri we designed a prospective study to evaluate the effect of SPI-1620 on spontaneously-occurring tumors in client-owned dogs as a phase 1 clinical trial. Dogs were evaluated via physical examination and hematologic assessment. SPI-1620 was injected intravenously over one minute, then laser Doppler probes (Periflux 4000®, Perimed AB, Sweden) measured perfusion in tumor and distant normal tissue for 3 hours. On day 7, SPI-1620 treatment was repeated followed 20 minutes later by chemotherapy. Escalating dosages of SPI-1620 were administered and the study is nearing completion. We have seen increases in tumor perfusion of up to 94% starting 17-20 minutes after SPI-1620 injection, with maximum effect by 1 hour and lasting for 3 hours post-injection. Perfusion to normal tissue is minimally affected. Responses have been seen in metastatic mast cell tumor and soft tissue sarcoma. Results were unexpected in that preclinical models did not suggest efficacy in mesenchymal tumors.
Rapamycin is the "father" of a group of drugs called rapalogs which inhibit the m-TOR pathway (mammalian Target Of Rapamycin). This pathway is primarily involved in sensing the nutrient conditions for a cell. Preclinical studies have shown activity of rapamycin in treating metastatic pulmonary osteosarcoma. Clinical studies in dogs have recently been completed through the Comparative Oncology Trials Consortium and data analysis is ongoing.
Oral malignant melanoma in dogs is a highly metastatic variant of this cancer. Unlike most tumors in which surface antigens are down-regulated just enough to escape detection by CD8+ cytotoxic T-lymphocytes, but conserve just enough to avoid elimination by natural killer cells, melanoma cells express a set of robust tumor-associated antigens (TAA) that are consistent across species. This expression of TAA allows manipulation of the immune system to improve recognition and elimination of cancer cells by the patient's immune effector cells.
IL-2 and IL-12 are considered "T cell growth factors" and promote proliferation and function of these immune effector cells. A multicenter clinical trial is currently ongoing at several Comparative Oncology Trials Consortium member institutions.
Conditionally approved by the USDA for administration by board-certified oncologists, the melanoma vaccine developed by Merial is the first vaccine approved in the treatment of cancer. Evaluation of this therapy (with added adjuvant of the cytokine GM-CSF to augment immune response) has shown that median survival times for stage 2-4 melanoma in the adjuvant setting exceeded 1.5-2 years (>833 days with preclinical formulations, and >569 days for locoregionally-controlled stage 2-3 tumors), which is a considerable increase over the 6-9 months that has historically been difficult to surpass. Furthermore it appears clear that local control must first be obtained by surgery and/or radiation therapy for the vaccine to produce the most beneficial effect.
This vaccine was developed based on the xenogeneic concept in which a TAA that is conserved across species is used from a different species in the species of interest, so that the immune system's response is augmented by the foreign source. Tyrosinase, an enzyme involved in melanin synthesis, and present regardless of melanin production (ie. present even in amelanotic melanomas) is the TAA used in the development of this vaccine, and human origin tyrosinase (87% homologous to canine tyrosinase) has been incorporated into the canine vaccine. The results of these investigations will hopefully lead to xenogeneic vaccination of human melanoma patients with murine tyrosinase. A recent unpublished update reported a 324 day median survival for controls and a median survival time that was not reached with an average follow up time of 411 days for dogs receiving the melanoma vaccine. Currently, evaluation of the additional field data that has been collected since the conditional approval is ongoing.
Nanoparticles are very small molecules (less than 30 nm) that adopt different interactions with matter as a result of their size. Uptake by cells and cellular effects can vary from the parent compound. At the University of Missouri we are evaluating gold nanoparticles for augmenting radiation therapy effects. Gold has a high mass which can increase local photoelectric effect from radiation therapy at the site of the tumor, decreasing scatter to nearby normal tissues. We are evaluating both systemic and local delivery, and delivery of non-radioactive particles in combination with external beam radiation therapy as well as delivery of radioactive gold nanoparticles.
Taxanes are anticancer drugs that are highly effective in human medicine for breast, GI, lung and other cancers. Their use is severely limited in veterinary medicine because of hypersensitivity reactions to carriers including Cremophor EL and Polysorbate 80. These reactions occur in people as well but can be managed. Nanoparticle formulation allows delivery of taxanes such as paclitaxel without the use of hypersensitizing carriers. Nanoparticle formulations are currently under investigation at the University of Missouri and at North Carolina State University in collaboration with participating institutions. If successful, these formulations would increase the scope of cancer treatment for animals to include an entire new group of drugs known to be effective against cancer. Additionally, research at Cornell University is underway investigating oral delivery of docetaxol in combination with cyclosporine to significantly increase oral bioavailability. This has allowed administration of standard formulations of docetaxol to be administered without adverse effects.
Bergman PJ, et al. Vaccine 24(21):4582-4585, 2006 (melanoma vaccine paper)
Gariboldi MD, Ravizza R, Molteni R, et al. Inhibition of stat3 increases doxorubicin sensitivity in a human metastatic breast cancer cell line. Cancer Letters 258 (2007) 181–188.
Wosikowski K, Lamphere L, Unteregger G, et al. Preclinical antitumor activity of the oral platinum analog satraplatin. Cancer Chemother Pharmacol 60:589-600, 2007.
Rajeshkumar NV, Rai A, Gulati A. Endothelin B receptor agonist, IRL 1620, enhances the anti-tumor efficacy of paclitaxel in breast tumor rats. Breast Cancer Research and Treatment (2005) 00: 1–11