Targeted Therapy with PI3 Kinase Inhibitors

Good treatments for cancer are most likely to be found in not just one “magic bullet,” but in a set of focused treatments known to the oncology team as targeted therapies.¹ In the same way in which a well-trained police team from the local precinct can work together with those they serve to bring an end to disorderly conduct, the oncologist and the treatment team work together to use the new targeted treatments to reduce the disruption of malignancy to normal life processes and improve quality of life. 

Human cancers can be arrested and malignant processes slowed significantly by anticancer agents known as the PI3 kinase (phosphatidylinositol-3-kinase) inhibitor drugs. Genetic changes that cause increased and uncontrolled activation of the PI3 kinase enzymes are commonly found in human tumors. The chemical pathway(s) that are catalyzed by these PI3 kinase enzymes are central to important life processes, including cellular growth, proliferation, and survival.² The PI3 kinases comprise a large extended family that has been divided into four classes (Class I–IV) (Table 1). The best studied have been the Class I enzymes and their Class IV relatives, such as mTOR (mammalian target of rapamycin).^3–5

Table 1: The PI3 Kinase Family^3–5

	Function	Characteristics
Class I	Phosphorylates phosphatidylinositol 4,5 bisphosphate [PI(4,5)(P2)] at the 3-OH position to produce  phosphatidylinositol (3,4, 5) trisphosphate [PI(3,4,5)P3(2)].	Alpha, beta, delta, gamma isoforms; isoform‑specific inhibitors may be useful anticancer agents
Class II	Phosphorylates additional phosphoinositides such as phosphatidylinositol (PI) and phosphatidylinositol-4-phosphate (PI4P)	Three catalytic isoforms (C2-alpha, C2-beta, and C2‑gamma).
Class III	Phosphorylates only phosphatidylinositol to generate phosphatidylinositol-3-phosphate (PI3P).	Vps34 (sole member). Involved in protein trafficking and vesicles. Activation of mTOR by amino acids.
Class IV	Phosphorylating enzymes related to PI3 kinase: mTOR; ATM (ataxia-telangiectasia mutated); ATR (ataxia telangiectasia mutated related) and DNA-PK (DNA-dependent protein kinase)	Monitors genomic integrity and/or integrates nutrient signaling to regulate cell growth.

For the PI3 kinase inhibitors, most adverse events are directly related to the specific molecular target in normal tissues inhibited or modulated by the specific drug. According to Paul Workman,⁶ toxicities are hard to predict but for the PI3 kinase inhibitors, which play a significant role in utilization of glucose by the cell, hyperglycemia and/or diabetes can be anticipated. In addition, rash (typical of the targeted therapies) is also likely.  The PI3 kinase (pan-isoform) inhibitor XL147 has demonstrated preclinical efficacy in a mutant xenografts assay, with a dose-limiting rash toxicity being reported in a 2009 trial with 48 patients.⁷  

Already in the clinic are mTOR inhibitor drugs such as temsirolimus (Torisel, Pfizer), and everolimus (Afinitor^®, Novartis) that are already being marketed and are in the hands of the majority of oncology practitioners. Although these drugs have definite value to clinicians, the adverse events, although acceptable in some patients, may result in dose reductions and reduced effectiveness in others.  These adverse events include myelosuppression, mouth ulcers, rash, fatigue, and metabolic abnormalities.  Non-infectious pneumonitis has also been observed.⁸

Some newer agents now in clinical trials are dual PI3 kinase/mTOR inhibitors. Serendipity played a role in the discovery of the duos, as a few of the dual PI3 kinase/mTOR inhibitors drugs were planned as solo PI3 kinase inhibitors. Companies such as Sanofi-Aventis (XL-765) and Novartis (BEZ‑235) discovered, however, that their compounds also inhibited mTOR. The hope for clinicians is that the combination will reduce the development of resistant mutations. Also useful are methods of identifying biomarkers that might predict resistance or sensitivity to cancers. For example, some data suggest that malignancies with KRAS mutations may not be sensitive to the PI3 kinase inhibitors.⁹

An alternative to the PI3 kinase/mTOR combinations are several pan-PI3 kinase inhibitor drugs which are specific for one or several PI3 kinase isoforms. Oncothyreon, for example, has developed a PI3 kinase inhibitor drug, PX866, which is selective for the alpha and beta p110 isoforms and is the only irreversible PI3 kinase inhibitor. PX866 is now in Phase 1 and Phase 2 clinical trials as monotherapy and also in combination with other anticancer treatments.¹⁰ In addition, another PI3 kinase p110 alpha inhibitor, licensed by Piramed to Genentech as GDC‑0941, is now in clinical trials.⁶

Inhibition of specific isoforms puts another tool in the hands of drug developers and anticancer specialists.  The hope is that the additional specificity will result in effective drugs with an acceptable safety profile. The PI3 kinase gamma enzyme may actually be a particularly promising target because blocking it would not likely produce many adverse events, according to scientific research just published in June 2011 Cancer Cell.¹¹

In addition, Calistoga Pharmaceuticals has recently developed a PI3 kinase delta agent, CAL-101, and preclinical trials in experimental and animal models suggest that the small molecule inhibitor may improve patient outcome in multiple myeloma.¹²

An approach just getting underway has been the design of combined PI3 kinase-MEK (mitogen‑activated protein kinase) inhibitors.^13–15 MEK, also referred to as MAPK kinase, is the focal point of many signaling pathways, including insulin signaling.  Research has shown that MEK inhibitors in combination with PI3 kinase inhibitors exert an anticancer effect that is much stronger than either drug alone.¹⁶    

Drugs that modulate and inhibit the PI3 kinases and closely related pathways may give us, at the very least, a better cancer cure. Although much of the excitement and interest surrounding these drugs is well founded, and the PI3 kinase inhibitors and assorted combinations promise to be important tools for all oncology clinical professionals, they may or may not be fully curative in all patients.⁹

REFERENCES

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11. Schmid MC, Avraamides CJ, Dippold HC, et al. ” Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3Kγ, a single convergent point promoting tumor inflammation and progression.” Cancer Cell. 2011;19(6):715-727.

12. Ikeda, et al. “PI3K/p110δ is a novel therapeutic target in multiple myeloma.” Blood. 2010 September 2; 116(9): 1460–1468.

13. Courtney KD, Corcoran RB, Engelman JA. “The PI3K pathway as drug target in human cancer.” J Clin Oncol. 2010;28(6):1075–1083.

14. Wong KK, Engelman JA, Cantley LC. “Targeting the PI3K signaling pathway in cancer.” Curr Opin Genet Dev. 2010;20(1):87–90.

15. Hoeflich KP, O’Brien C, Boyd Z, et al. “In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models.” Clin Cancer Res. 2009;15(14):4649–4664.    

16. American Association for Cancer Research. “Combination Targets For Cancer: Some Drugs Work Well Together, Studies Suggest.” ScienceDaily, 24 Oct., 2007. www.sciencedaily.com/releases/2007/10/071024115312.htm. Accessed January 25, 2012.