Abstract PL08-01: Clinical achievements reached by interfering with the IGF1R-PI3K-PTEN-AKT-mTOR axis.
Authors: Dittrich Christian 
Published: June 2012

Abstract
The investigation of tumor metabolism has been in the focus of scientists like Warburg since almost a century. In the 1950s, the role of glutamine as a tumor nutrient has been recognized. Both, glucose and glutamine, regarded as key elements of metabolism of highly proliferating tumor cells, and their fate in the human organism were targets of extensive biochemical investigations over decades without leading to therapies with sufficient impact on patients' outcome. Recently when it has been found, that oncogenes are influencing glucose and glutamine metabolism, these nutrients got attention from oncologists.
The phosphatidylinositol 3-kinase (PI3K) signaling axis has been identified as a key signal transduction system linking oncogenes and multiple receptor classes to essential cellular functions, among them cancer cell growth, survival, motility, and metabolism. It is impossible to dissect the relative contribution of the pathway to the net effect of each of the above enumerated functionalities; the same is true for the therapeutic intervention via inhibiting agents on this pathway.
Several insulin-like growth factor receptor inhibitors, monoclonal antibodies or small molecule tyrosine-kinase inhibitors, have entered phase I to III. Since only modest clinical activity was observed with the drugs as single agents (objective remissions in Ewing sarcoma and leukemia patients), their combination with cytotoxic agents was tested extensively. So far, no definitive clinical superiority of any anti-IGF-1R in any tumor entity is available. The most advanced clinical trial program of an anti-IGF-1R directed therapy is the one testing figitumumab (CP-751,871). Despite promising phase II results with an overall response rate of 64% in combination with paclitaxel-carboplatin standard therapy in not pretreated NSCLC, the consecutive phase III study was stopped early for futility. Similar happened to a phase III study comparing figitumumab combined with erlotinib to erlotinib alone in the second-line setting of NSCLC. Among the most frequent class side-effects observed was disturbance of glucose metabolism in form of hyperglycemia. Some molecules dispose on hematotoxicity, preponderantly in form of thrombocytopenia. Hypersensitivity reactions were rare and usually of low grade. Decrease in IGF-R, pAKT, pMAPK and pS6 (especially generated with MK-0646 (dalotuzumab)) can be interpreted as proof of mechanism of action of this therapeutic approach. Whether the change in their expression reflects their potential relevance as biomarkers, reflecting clinical activity of the respective agent tested, is to be determined. A proof of concept is still outstanding.
The PI3K pathway is one of the most commonly activated pathways in human cancer. Many of its components are frequently mutated or altered in form of e.g. presence of constitutively active mutants or amplification of receptor tyrosine kinases or amplification of PI3K or presence of activating mutations in the PIK3CA gene, or over-expression of AKT or loss/occurrence of inactivating mutations of the PTEN gene. Due to its central position concerning the regulation of the cell function, it was avoided to target the axis therapeutically, especially in order not to interfere with its physiologic role with the insulin metabolic signaling. According to their substrate preference and sequence homology, PI3Ks are grouped into three classes (I-III), each disposing on distinct roles in signal transduction. Kinases belong to the most “druggable” classes of intracellular components and represent therewith ideal targets for the development of tailored small molecular inhibitors. PI3K inhibitors can be divided into isoform-specific inhibitors or pan-PI3K inhibitors. The latter target all class IA PI3Ks. Among them are PX-866, which targets the PI3K isoforms α, δ, γ, and has undergone phase I and II testing yielding disease stabilization in 7/31 advanced solid tumor patients. Among the pan-inhibitors of class I PI3Ks are the molecules NVP-BKM120, XL147, and GDC-0941. BKM120 has undergone phase I testing and reached MTD. Pharmacodynamic effects, e.g. in form of suppression of S6 phosphorylation in skin, was documented as well as clinical activity observed (2 PRs, 7/35 patients on study ≥8 months). XL147 had rash as DLT, accompanied with one PR in NSCLC and 6/39 patients stable for &gt;6 months in advanced solid tumors. The development of GDC-0941 is one of the most advanced. MTD was reached with hyperglycemia, skin toxicity in form of rash, and thrombocytopenia as DLTs. A correlative equivalent of clinical activity by functional imaging in form of FDG-PET could be established. But, the lack of substantial clinical activity identified the compound to be used merely for combination therapy, e.g. with bevacizumab or trastuzumab and trastuzumab-MCC-DM1. The latter combinations deduce their rationale from acquired resistance to receptor tyrosine kinases, e.g. of the HER-family, leading to a switch thereby activating the PI3K pathway as compensatory mechanism. The up-front combination of the PI3K inhibitors with EGFR inhibitors could both increase the benefit of EGFR inhibitors and delay the development of resistance. This has led to the clinical testing of a variety of combinations of PI3K inhibitors and RTK inhibitors, but also of inhibitors of single further steps of the RAS-RAF-MEK-ERK pathway. These efforts yielded limited clinical activity and partly supra-additive overlapping toxicity accompanied with a lack of reliable pharmacodynamic markers for the plethora of combinatorial effects created by permutation of the substances tested. Whereas pan-PI3K inhibitors target all class IA PI3Ks, isoform-specific inhibitors allow focused complete target inhibition and simultaneously restricting side-effects. Whether this theoretical advantage of using a p110α-specific inhibitor shows an advantage in the treatment of cancers with PIK3CA mutations or in breast cancers with ERB-B2 mutations is still to be proven clinically. The actual clinical most advanced developed example of an isoform-specific PI3K inhibitor is the isoform δ specific inhibitor CAL-101. This isoform is restricted to immune cells. Therefore, the compound was tested in patients with chronic myelogenous leukemia yielding responses in about half of them. The median PFS in 51 heavily pretreated bad prognosis patients was exceeding 11 months. In 30 pretreated patients with indolent non-Hodgkin lymphoma, the median PFS exceeded 11 months as well. Combination with bendamustine or retuximab was clinically effective and tolerable.
There exists no more central molecule than PTEN which disposes on tumor-suppressing activity. Little is known about the mechanism of its regulation. It is noteworthy, that no success in directly targeting PTEN therapeutically has been reported so far.
AKT is negatively regulated by PTEN. AKT mediates the phosphorylation and activation of the mTOR complex 1 (mTORC1). Because of this crucial position in the pathway, several AKT inhibitors have been developed. The clinically most advanced inhibitor perifosine is a phosphatidylinositol analogue which prevents AKT from binding to PtdIns(3,4,5)P3. In a prospective randomized phase II trial in patients with refractory colorectal cancer, the combination of perifosine and capecitabine resulted in improved time-to-progression and overall survival compared to capecitabine alone. MK-2206 is an allosteric pan-AKT inhibitor which in a phase I study showed stable disease in 6/19 patients and decreases in CA-125 levels in ovarian cancer. Among the most prominent side-effects were rash, and hyperglycemia.
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates cell growth and metabolism in response to environmental stimuli. mTOR consists of two multi-protein complexes. The development of the so-called rapalogs represents a shift of paradigm in solid tumor oncology towards target-orientated therapy. This led to the registration of temsirolimus by FDA and EMA for the treatment of previously untreated patients with metastatic renal cell carcinoma and poor prognosis, based on improved overall survival (hazard ratio for death: 0.73 [95%CI 0.58–0.92]; p=0.008). In a next step, everolimus was registered by FDA and EMA for the treatment of patients with metastatic renal cell carcinoma, that had progressed on other targeted therapies, based on prolonged PFS (median PFS: 4.0 months [95%CI 3.7–5.5] vs 1.9 [1.8–1.9]). In addition, everolimus reached improved PFS in advanced pancreatic neuro-endocrine tumors with a median of 11 months compared to the placebo with 4.6 months (hazard ratio for disease progression or death: 0.35 [95%CI 0.27–0.45]; p&lt;0.001). The high response rate of 40% in refractory mantle-cell lymphoma was justification for EMA to register temsirolimus for this rare indication. A further rapalog, ridaforolimus, is actually undergoing phase I-III trials. A new generation of mTOR inhibitors targets not only mTORC1, but both mTOR complexes. Agents like BEZ235, XL147, or PKI-587 are dual PI3K/mTOR inhibitors. Whereas mTORC1 inhibitors (rapalogs) often lead to a feedback activation of PI3K, dual PI3K/mTOR inhibitors might mitigate this feedback activation. Whether this will yield improved clinical results is still to be proven.
Although the development of inhibitors of the PI3K-AKT-mTOR axis can be judged as very successful, especially when focusing on that of rapalogs, the future developments should be based more on the integration of early patient selection, mainly via molecularly defined pathway deviations, identified by standardized and early validated biomarkers for prediction to allow a more rational and therewith more rapid and cost-effective drug development in this area of oncology.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr PL08-01.