NEW CANCER DRUGS IN PIPELINE

November 19, 2009 — Innovations in drug development, target selection, and new discoveries in molecular and cell biology have had a profound affect on cancer therapy. During a press briefing at the Molecular Targets and Cancer Therapeutics international conference, sponsored by the American Association for Cancer Research, the National Cancer Institute, and the European Organization for Research and Treatment of Cancer, researchers gave an overview of several new compounds that are in preclinical or early-phase trials.

The presentations included information on the role of heat shock protein 70 (hsp70) as a novel therapy for breast cancer, compounds that target leukemia stem cells, tolerability results of the experimental agent cediranib (AstraZeneca) for use in pediatric recurrent or refractory solid tumors, and sensitivity results in colorectal cancer with the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib (AstraZeneca), which has already shown promise in breast cancer.

"This research spans studies on the genetic make-up of cancer cells, validation studies on the roles of key signaling proteins and pathways, the development of novel agents, and the testing of those agents in a variety of preclinical and clinical settings," said session moderator Sara A. Courtneidge, PhD, DSc, professor and director of the Tumor Microenvironment Program and director of academic affairs at the Burnham Institute for Medical Research, La Jolla, California, in a statement.

Novel Therapy for Breast Cancer

Preclinical in vitro and in vivo studies have shown that targeting heat shock response proteins with panobinostat (Novartis), combined with an autophagy inhibitor, has promise as a novel treatment strategy in breast cancer.

Panobinostat is an experimental agent that selectively inhibits the enzyme histone deacetylase, which leads to apoptosis of malignant cells through multiple pathways.

One of the hallmarks of cancer is the stress phenotype, explained study author Kapil Bhalla, MD, director of the Medical College of Georgia Cancer Center in Augusta. The stress phenotype is collectively induced by hypoxia, deprivation of nutrients, acidosis, and increased reactive oxygen species, and is exhibited as metabolic and protein misfolding/denaturing stress. This process leads to the constitutive activation of the heat shock response, with elevated levels of heat shock proteins and induction of autophagy.

Elevated levels of hsp70 and hsp90 promote proper protein folding and inhibit both the intrinsic and extrinsic pathways of apoptosis. "The focus of this work was how hsp70 regulates the process of autophagy," said Dr. Bhalla.

Dr. Bhalla and colleagues evaluated the stress phenotype of breast cancer cells in vitro and in vivo. They first determined that, in the in vitro setting, the stress induced by nutrient withdrawal or treatment with panobinostat resulted in hyperacetylation of hsp70, which in turn induced autophagy in cultured breast cancer MB-231 and MCF-7 cells.

To determine the in vivo role of hyperacetylated hsp70 in autophagy, the researchers obtained tumor cell lysates that had grown in the mammary fat pads of nonobese diabetic (NOD)/severe combined immunodeficiency (SCID) mice implanted with MB-231 xenografts. Cells were analyzed from tumors of various sizes, and the reseasrchers found that there was a size-dependent increase in the intracellular levels of hyperacetylated hsp70, as well as in Beclin1 and LC3II, both markers of autophagy.

Collectively, they note, these findings suggest that the stress-phenotype-associated heat shock response and the increase in acetylated hsp70 promotes autophagy. The findings also demonstrate that in established breast cancers, autophagy can be selectively targeted by cotreatment with agents such as panobinostat and an autophagy inhibitor.

Identifying Compounds That Target Leukemia Stem Cells

Sean McDermott, PhD, research investigator in the Department of Internal Medicine, Hematology-Oncology at the University of Michigan Medical School in Ann Arbor, discussed how his team identified a new paradigm for screening against leukemia stem cells.

"We wanted to identify compounds that would specifically target leukemia stem cells and hopefully not target normal blood-forming stem cells at the same time," said Dr. McDermott. "In the end, we were able to screen a library of 4000 small molecules that have been used by numerous other labs and companies over the past 10 years and came up with 3 compounds."

Instead of using traditional cell lines, the researchers screened a collection of 4000 known bioactive, off-patent, and natural compounds against 2 leukemia cell lines. They initially identified 76 compounds that were positive against both lines and, because leukemia stem cells share some pathways with hematopoietic stem cells (HSCs), the researchers counter-screened potential hits on normal HSCs and progenitor cells, identifying only 10 compounds.

Of these 10, 3 targeted stem cells — ciclopirox olamine, etoposide, and kinetin riboside. When tested against cell lines of primary acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML), kinetin showed efficacy at levels similar to the AML chemotherapeutics cytarabine and mitoxantrone. In 2 of 4 samples, kinetin riboside inhibited engraftment of primary AML cells in NOD/SCID mice.

Ciclopirox olamine, a clinically used antifungal, targets stem cells by chelating intracellular iron and inhibiting the ribonucleotide reductase enzyme, without harming normal HSCs.

The third agent, etoposide, was screened with cells obtained from 51 patients with AML and 12 patients with CML. "We were amazed by it," said Dr. McDermott. "We saw a huge range of responses in AML and CML."

Etoposide was effective in vitro on 29% (15 of 51) of primary AML cells and 67% (8 of 12) of CML cells, and inhibited the NOD/SCID mouse engraftment of 3 responsive AML samples. "We looked at responders and nonresponders, and saw a dramatic response only in responders," he said. "At this time, it seems possible to identify patients who might benefit from etoposide treatment clinically."

Early Cediranib Study Promising in Pediatric Patients

Preliminary evidence shows that cediranib might have activity in childhood sarcomas; in addition, it appears safe, with tolerable adverse effects. To date, 3 of the 13 patients enrolled in the phase 1 trial have experienced partial shrinkage of their tumor, and the 12 mg/m² once-daily dose was found to be tolerable.

Cediranib is an orally bioavailable small-molecule inhibitor of the tyrosine kinase activity of vascular endothelial growth-factor receptor (VEGFR)-1 (Flt-1), VEGFR-2 (KDR), VEGFR-3 (Flt-4), and c-KIT. The goal of this study was to determine the toxicity profile, dose-limiting toxicities, maximum tolerated dose, pharmacokinetics, and pharmacodynamics of cediranib in a population of children and adolescents with relapsed or refractory solid tumors.

"Our end points were pretty standard for a phase 1 trial," said study author Elizabeth Fox, MD, MSCR, a staff clinician in the Pediatric Oncology Branch at the National Cancer Institute. "We were also monitoring for an objective response, using RECIST [Response Evaluation Criteria in Solid Tumors] and [World Health Organization] criteria."

Patient diagnoses were Ewing's sarcoma (n = 3), osteosarcoma (n = 2), alveolar soft part sarcoma (n = 2), synovial sarcoma (n = 2), and other solid tumors (n = 4).

It is always exciting to see an objective response in a phase 1 trial, Dr. Fox pointed out. A patient with Ewing's sarcoma, who was treated at the lowest dose level of 8 mg/m², experienced more than a 70% reduction in tumor volume. In addition, partial responses were seen in 2 patients with synovial sarcoma at the 12 mg/m² daily dose.

Adverse events in this population were similar to those seen in adults taking cediranib, Dr. Fox noted. Nondose-limiting toxicities included anorexia, fatigue, diarrhea, abdominal pain, nausea, headache, rash, increased thyroid-stimulating hormone, decreased left ventricular function, and proteinuria.

Two patients have completed 1 cycle of cediranib 17 mg/m² daily, with 1 patient experiencing grade 3 nausea (dose-limiting toxicity).

The researchers are currently evaluating the effects with 17 mg/m² of cediranib and have proposed to the Children's Oncology Group that a phase 2 study be conducted in selected childhood solid tumors.

PARP Inhibitor Olaparib for MSI Colorectal Cancer

As previously reported by Medscape Oncology, early research shows that the PARP inhibitor olaparib demonstrated antitumor activity in breast, ovarian, and prostate cancers associated with BRCA1 and BRCA2 mutations. Researchers now report that olaparib showed activity against cell lines of homologous recombination-deficient MRE11 mutant microsatellite instable (MSI) colorectal cancer.

"It's been where we see the greatest levels of homologous recombination deficiency that we've been able to focus phase 2 trials," said study author Mark O'Connor, PhD, chief scientist at KuDOS Pharmaceuticals Ltd, Cambridge, United Kingdom. "There are currently phase 2 trials ongoing in triple-negative breast cancer and serous ovarian cancer."

Cells that are deficient in homologous recombination DNA repair or signaling pathways are potentially sensitive to PARP inhibition; examples include inactivating MRE11 mutations that have been linked to mismatch-repair-deficient MSI colorectal and endometrial cancers.

A proportion of colorectal cancers have microsatellite instability, explained Dr. O'Connor. "What we wanted to do was to test whether or not colorectal cancer cells that were MRE11 deficient and microsatellite unstable were more sensitive to olaparib than those that weren't," he said.

The analyses by Dr. O'Connor and colleagues revealed that MRE11 mutant and MSI colorectal cells were sensitive to olaparib treatment, whereas microsatellite stable MRE11 wild-type cells remained insensitive. All olaparib-sensitive colorectal cancer cell lines were homologous recombination deficient, and they confirmed that the loss of MRE11 expression can confer sensitivity to olaparib.

These results provide evidence and suggest that patients with MSI and MRE11-deficient colorectal cancer could be suitable candidates for treatment with olaparib, the authors note.

American Association for Cancer Research (AACR), the National Cancer Institute (NCI), and the European Organization for Research and Treatment of Cancer (EORTC) Molecular Targets and Cancer Therapeutics International Conference: Abstracts B21, A51, A5, A114. Presented November 16, 2009.