More than 80 years ago, Nobel laureate Otto Heinrich Warburg pointed to a difference in mitochondrial energy metabolism between tumour cells and normal healthy cells. This observation led to significant advances in cancer imaging using positron emission tomography (PET) and, because the altered energy metabolism is common to many types of cancer cells but not normal cells, it is also an attractive target for therapy. Now, Cornerstone Pharmaceuticals has announced the start of a clinical trial with a ‘thioctan’, CPI-613, the first example of an altered energy metabolism-directed (AEMD) compound.
In laboratory tumour models and animal studies, the new class of compounds were effective, even against difficult to treat tumours such as those of the lung, colon and pancreas, and showed very few adverse effects.
The inventors describe key differences between metabolism in normal cells compared to that in cancerous cells:
The vast majority of normal cells utilize a single metabolic pathway to metabolize their food. The first step in this metabolic pathway is the partial degradation of glucose molecules to pyruvate in a process known as glycolysis or glycolytic cycle. The pyruvate is further degraded in the mitochondrion by a process known as the tricarboxylic acid (TCA) cycle to water and carbon dioxide, which is then eliminated. The critical link between these two processes is a large multi-subunit enzyme complex known as the pyruvate dehydrogenase (“PDH”) complex (“PDC”). PDC functions as a catalyst which funnels the pyruvate from the glycolytic cycle to the TCA cycle.
Most cancers display profound perturbation of energy metabolism. This change in energy metabolism represents one of the most robust and well-documented correlates of malignant transformation.
Because tumor cells degrade glucose largely glycolytically, i.e. without the TCA cycle, large amounts of pyruvate must be disposed of in several alternate ways. One major pathway used for disposal of excess pyruvate involves the joining of two pyruvate molecules to form the neutral compound acetoin. This generation of acetoin is catalyzed by a tumor-specific form of PDC. Although the TCA cycle still functions in cancer cells, the tumor cell TCA cycle is a variant cycle which depends on glutamine as the primary energy source. Tumor-specific PDC plays a regulatory role in this variant TCA cycle. Thus, inhibition or inactivation of a single enzyme, namely tumor-specific PDC, can block large scale generation of ATP and reducing potential in tumor cells.
In the rare inherited human disease, ataxia-telangiectasia (A-T), a mutation is present in a gene encoding a protein that normally activates cellular responses to DNA damage. The mutation in the ATM gene leads to decreased ability to repair damaged DNA, and an increased sensitivity to ionising radiation and other DNA damaging agents. This highlights the ATM pathway as a potential target to increase the sensitivity of tumour cells to radiotherapy or chemotherapy. The ATM protein demonstrates kinase activity and a selective, small molecule inhibitor of this kinase, CP466722, has now been shown to enhance the sensitivity of tumour cells grown in vitro to ionising radiation.
Inhibition of ATM kinase activity is rapid, and is completely and rapidly reversed on wash-out; further experiments suggested that inhibition of ATM for a short period of time may be sufficient to sensitise tumour cell to radiotherapy. Because CP466722 is effective in murine cells as well as human cells, it may be possible to use mouse models to further explore the potential of using ATM inhibitors to increase the effectiveness of radiotherapy.
A new study describes a high affinity interaction between siramesine and phosphatidic acid, a component of cell membranes that also acts as a signalling molecule. Siramesine is a sigma receptor agonist, selective for the σ2 subtype, which was originally under development for the treatment of anxiety but failed to show efficacy in clinical trials.
Siramesine was subsequently shown to kill cancer cells by destabilising their lysosomes. Vincristine, a microtubule destabilising antimitotic drug, which is used in various chemotherapy regimens, greatly sensitised cancer cells to the cytotoxic effects of siramesine.
The new study suggests that it may be possible to design small molecules to specifically scavenge phospholipids involved in the signalling cascades controlling cell survival.
Prostate cancer is the most common cancer in men, with the majority of cases occurring in the over-65s. Rising levels of prostate specific antigen (PSA) are associated with both localized and metastatic prostate cancer and a blood test for PSA is used for the early detection of the disease.
A recent study suggests that regular use of non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen may reduce measured serum PSA levels, although it was unclear whether this indicated a protective effect against prostate cancer or whether use of NSAIDs obscured the test results. Paracetamol, which has very little anti-inflammatory activity, did not show a statistically significant effect on serum PSA levels.
Since prostate cancer cells show unusually high levels of the enzyme COX-2, which is inhibited by NSAIDs, there is considerable interest in the potential for COX-2 inhibitors in the treatment of prostate cancer and several clinical studies have been initiated.
Angiotensin Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs) were developed primarily to treat hypertension, but several recent studies have shown that they could have additional benefits.
In one study, mice in which the gene for ACE had been deleted were found to have lower body weight and a lower proportion of body fat than their wild type litter mates. The decreased body fat in the ACE knock-out mice was independent of food intake and appeared to be due to increased metabolism of fatty acids in the liver, with an additional effect of increased glucose tolerance.
Another study found that use of either ACE inhibitors or Angiotensin Receptor Blockers (ARBs) significantly reduced basal cell carcinoma and squamous cell carcinoma in patients at high risk of these keratinocyte cancers.
High levels of Angiotensin II have also been linked to the pro-angiogenic protein, vascular endothelial growth factor (VEGF) in pancreatic ductal adenocarcinoma (PDA).
An ARB significantly inhibited the Angiotensin II induced increase in VEGF in PDA cell lines and, in an earlier study, an ACE inhibitor was shown to have a similar effect. These studies suggest that ACE inhibitors and ARBs may represent potential novel and promising strategies for controlling angiogenesis, prevention of metastasis, and prolongation of survival in patients with primary or metastatic PDA.
A recent report suggests that treatment with a combination of two commonly used anti-cancer drugs, doxorubicin and zoledronic acid, may benefit women with breast cancer. Doxorubicin is an anthracycline antibiotic that is widely used in cancer chemotherapy. It is thought to work by intercalating DNA and preventing cell replication.
Zoledronic acid is a third generation bisphosphonate that is used to prevent fractures in cancer patients with bone metastases. The bone destruction associated with malignancy develops because tumor cells synthesize and release soluble factors that stimulate osteoclasts to resorb bone. The bisphosphonate drugs act by inhibiting osteoclast function.
Zoledronic acid and other bisphosphonates are also used to treat osteoporosis – a single dose of zoledronic acid has been shown to increase bone mineral density for up to a year.
The new study looked at the effects of the two drugs given alone, sequentially , or in combination on the growth of established breast tumours in mice. Alone out of the treatment methods, doxorubicin followed 24 hours later by zoledronic acid almost completely abolished tumor growth in the absence of bone disease. Zoledronic acid has already been shown to reduce the risks of fractures in breast cancer patients with bone metastases and the new study provides hope that new dosing regimens may provide additional benefits.
Telomeres are repetitive sequences at the 3’-end of DNA which protect the end of the chromosome from destruction during cell division. During the process, the telomeres are themselves destroyed and this mechanism normally limits cells to a fixed number of divisions. Embryonic stem cells express an enzyme, telomerase, which replaces the telomeres and allows the cells to divide repeatedly. Telomerase remains active in some rapidly dividing adult cells, but is switched off almost completely in most other cells to prevent excessive proliferation. Cancer cells often regain telomerase activity and are able to replicate indefinitely. Telomerase activity has been observed in approximately 90% of human tumours and inhibition of this enzyme is seen as a potential treatment for many cancers.
The telomerase is a reverse transcriptase that carries its own RNA primer sequence and has some similarities to the retroviral reverse transcriptases, viral RNA polymerases and B-family DNA polymerases. The first telomerase inhibitor to enter clinical trials for the treatment of cancer is GRN163L, a lipid-conjugated thiophosphoramidate. GRN163L is resistant to nuclease digestion in blood and tissues and has very high affinity and specificity for telomerase.
Small molecule inhibitors such as BIBR1532, which inhibits telomerase activity in vitro with an IC50 in the low nanomolar range, have also been identified. The nucleoside analogue AZT, which is used to treat HIV by inhibiting the viral reverse transcriptase, weakly inhibits telomerase activity. An advance online publication in the journal Nature describes a high resolution structure of the Tribolium castaneum catalytic subunit of telomerase, TERT (Telomerase Reverse Transcriptase).
It is hoped that the new structure will help in the design of small molecule telomerase inhibitors. As well as de novo design, the similarity between TERT and HIV reverse transcriptase suggests that it may be possible to modify reverse transcriptase inhibitors to inhibit telomerase. Such compounds could potentially be used to treat a wide range of cancers.
Rapamycin is a macrolide antibiotic used as an immunosuppressant to prevent organ rejection in transplant patients. Rapamycin and analogues have also been found to have anti-proliferative properties and their effects have been studied in a variety of cancers. Despite early promise, however, clinical tests have proved less successful than had been hoped.
A report in the Journal of Clinical Investigation now suggests a reason for this lack of success. The anti-tumour effects of rapamycin are brought about by inhibition of the mTORC1 (mammalian target of rapamycin complex 1) pathway which is activated in many cancers, but the new study shows that this inhibition leads to activation of the mitogen-activated protein kinase(MAPK) cascade which stimulates the growth of cancer cells. The authors showed that the MAPK inhibitor, PD0325901, enhanced the effect of rapamycin or an analogue, RAD001 in cancer cell lines, and a xenograft mouse model of cancer.
The results suggest that patient stratification based on molecular pathways and combined use of these drug families, both of which are currently used as single agents in the clinic, will provide more effective treatments for cancer.
The mTOR (mammalian target of rapamycin) pathway represents a convergence point for signalling pathways commonly disrupted in cancer. The pathway includes several known and putative oncogenes as well as tumour suppressors. Rheb GTPase is the upstream activator of the mTOR Complex 1 (mTORC1) and is itself activated by growth factors and nutrients.
Two independent papers in the August 15th issue of Genes and Development link Rheb activity with particular cancers. Wendel et. al. demonstrate that Rheb activation can produce rapid development of aggressive and drug-resistant lymphomas. The authors further show that activation of mTORC1 is dependent on farnesylation of Rheb and that an inhibitor of farnesyl transferase (FTI) is able to block the activation. It is noted that Rheb is highly expressed in certain human lymphomas.
Pandolfi et. al. show that overexpression of Rheb promotes hyperplasia and a low-grade neoplastic phenotype in the mouse prostate. Additionally, Rheb overexpression combined with Pten haploinsufficiency results in marked promotion of prostate tumorigenesis.
These results suggest potential for Rheb as a therapeutic target in particular oncology indications.
Polo-like kinase 1 (Plk1) has received attention in recent years as a potential target for intervention in cancer. It is known to be important in regulation of cell cycle progression during M-phase and has been shown to be overexpressed in certain tumours. Now scientists at the NYU Cancer Institute and Howard Hughes Medical Institute have shown that Plk1 is involved in a new pathway associated with the cellular response to DNA damage. In the July 25th issue of Cell, the authors describe targeting of the phosphatase Cdc14B to APC/C, a protein that marks other proteins for destruction. The resultant activated APC/C then tags Plk1 for destruction. If Plk1 remains active, the cell continues to divide despite the DNA damage.
Tekmira Pharmaceuticals, a specialist in delivery of RNA interference molecules, has just announced plans to advance an siRNA product targeting Plk1 into Phase 1 clinical trials in the second half of 2009. Meanwhile, the search for small molecule inhibitors of Plk1 continues. Scientists at Pfizer deposited x-ray coordinates of the catalytic domain of a mutant Plk1(complexed with BI2536) in the protein data bank earlier this year. Additional structure factors have been deposited by Sunesis scientists, although the coordinates have not yet been released.