Advances in the understanding of the molecular basis of cancer have led to the identification of key pathways involved in tumour initiation and progression, and translating this innovative science into the next generation of therapeutic agents remains one of the major hurdles to meaningful improvements in cancer treatment. While clinical successes remain extremely challenging to achieve, increasing numbers of targeted agents are emerging through clinical trials and making differences in the lives of patients. In this symposium several new clinical agents for targeted therapies were presented. Firstly Kui Lin from Genentech presented a new pan-Akt inhibitor, GDC-0068.

Akt is one of the most frequently activated protein serine/threonine kinases in human malignancies. As a central node of the PI3K-Akt-mTOR pathway, Akt plays a critical role in cancer initiation, progression and therapeutic resistance, representing an important and attractive cancer therapeutic target.

Initial optimization of inhibitors, identified from a high-throughput screen against Akt1, led to potent pan-Akt inhibitors with poor selectivity over other kinases (e.g., the closely related protein kinase A, PKA). However subsequent optimization of pharmaceutical properties led to the discovery of GDC-0068, a potent, orally bioavailable, ATP-competitive pan-Akt inhibitor that is highly selective over other kinases.

GDC-0068 blocks Akt signaling as demonstrated by dose-dependent inhibition of the phosphorylation of multiple downstream targets of Akt in human cancer cell lines. In addition, GDC-0068 inhibits cell cycle progression and viability of cancer cell lines driven by Akt signaling, including those with defects in the tumour suppressor PTEN, oncogenic mutations in PIK3CA, and amplification of HER2. Antitumor efficacy was observed in multiple xenograft tumor models, including those of human prostate, breast, ovarian, colon, glioma and melanoma origins. Tumour stasis or regression was achieved at well-tolerated oral doses in xenograft models predicted to be dependent on activated Akt signaling. Consistent with the role of Akt in a survival pathway, GDC-0068 also demonstrated enhanced antitumor efficacy when combined with other therapeutic agents.

In summary, GDC-0068 is a novel, highly selective ATP-competitive Akt inhibitor with compelling selectivity, efficacy, and oral pharmacokinetics that support its clinical development as an anti-cancer agent. The selective activity in cancer cells with activated Akt signaling allows for a rational strategy to potentially identify patients who will benefit in clinical trials. GDC-0068 is currently in phase I clinical trials in cancer patients.

Next Jason Damiano from Novartis Pharmaceuticals discussed the Preclinical development of LFA102, a highly potent and selective neutralizing antibody against the prolactin receptor.

The prolactin receptor (PRLR) is frequently expressed in breast and prostate cancer. The polypeptide hormone prolactin (PRL) has been demonstrated to induce PRLR signaling leading to cell proliferation and survival. Tissue specific overexpression of PRL in animal models leads to a higher incidence of mammary and prostate tumours, respectively. Elevated serum PRL levels in humans have been correlated with an increased risk for breast cancer, and an analysis of more than 3000 breast tumor specimens indicates that PRLR is expressed with high prevalence (60-70% of tumors) across all breast cancer subtypes. In prostate cancer specimens, the presence of prolactin has been reported to be associated with high-grade tumours and poor clinical outcomes, suggesting a role of the PRL/PRLR signaling pathway in the pathology of this disease.

Thus the idea to target the PRL/PRLR axis may be a new approach for addressing unmet medical need in these tumor types. LFA102 is an anti-PRLR antibody and in vitro studies have shown that LFA102 can show antitumor activity in vivo by mediating antibody-dependent cellular cytotoxicity (ADCC) and inhibit the PRL-dependent release of the proangiogenic factor VEGF from breast cancer cells. Preclinical toxicological studies of LFA102 indicate that this therapeutic is well tolerated and exhibits a normal pharmacokinetic profile in relevant animal species. The safety and pharmacokinetics of LFA102 in humans are currently being evaluated in a phase I healthy volunteer trial. A phase 1b trial in breast and prostate cancer is planned to evaluate the efficacy of this antibody in patient populations predicted to have the highest probability of benefiting from an anti-PRLR therapeutic.

Finally in this session Christian Rommel from Intellikine presented a novel TORC1/2 kinase inhibitor (INK128). mTOR kinase comprises two distinct multi-protein complexes, TORC1 and TORC2, which together regulate processes critical for cell growth and survival. Targeting the mTor pathway is the basis of many cancer drugs such as temsirolimus and everolimus, pharmaceutical derivatives of rapamycin. Through rational drug design we have identified INK128, a potent and selective small molecule, active-site kinase inhibitor of mTOR with excellent drug-like properties. mTOR has been implicated in the tumorigenesis of metastatic renal cell carcinoma (RCC) and so we decided to investigate INK128 in preclinical in vitro and in vivo models of renal cell carcinoma (RCC) and to compare its activity to other agents commonly used to treat this disease.

In mouse tumor models, INK128, rapamycin, avastin and sorafenib displayed anti-tumour efficacy; however, they differ in the mechanisms underlying the anti-tumour activity. INK128 and rapamycin suppressed tumour growth by directly inhibiting tumour cell proliferation; however neither had much impact on tumor-associated angiogenesis. In contrast, sorafenib and avastin suppressed tumour growth by potently inhibiting tumour angiogenesis. The activity of the combination of INK128 with sorafenib or avastin yielded sustained tumor regression by targeting tumour cells and the microenvironment.

In conclusion INK128 offers a novel approach for the treatment of renal cell carcinoma by targeting TORC1/2 signaling. Additionally, the mechanism of action of INK128 is different than current therapies and may not display cross-resistance with current standard of care agents.