FIND DRUGS:

BRAND NAME GENERIC NAME INDICATION MANUFACTURERS COMPARE DRUGS

Targeted Therapy with PI3 Kinase Inhibitors

Share this article:
Targeted Therapy with PI3 Kinase Inhibitors
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 Family3–5


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

1. Strebhardt K, Ullrich "A. Paul Ehrlich's magic bullet concept: 100 years of progress." Nat Rev Cancer. 2008;8(6):473-480.

2. Vimalanathan AB, Raja AK, Tyagi MG. "The role of PI-3 kinase in cancer biology and approaches to the therapeutics of cancer." Biology and Medicine. 2009;1(4)Rev1:1-13.

3. Foster FM, Traer CJ, Abraham SM, Fry MJ.  The phosphoinositide (PI) 3-kinase family. J Cell Sci. 2003;116(Pt 15):3037-3040.

4. Haas J. "It's apples versus oranges in the PI3 Kinase race." Start-Up. Oct 2009:1–3.

5. Ihle NT, Powis G. "Take your PIK: phosphatidylinositol 3-kinase inhibitors race through the clinic and toward cancer therapy." Mol Cancer Ther. 2009;8(1):1-9.

6. Miller N. "BACR Interview #4: Professor Paul Workman (Piramed Pharma/Chroma Therapeutics)". Beremans Ltd. 2009. www.beremans.com. Accessed January 25, 2012.

7. Baselga J. "Targeting the phosphoinositide-3 (PI3) kinase pathway in breast cancer." Oncologist. 2011;16 Suppl 1:12-19.

8. Yuan R, Kay A, Berg WJ, Lebwohl D. "Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy." J Hematol Oncol. 2009;2:45.

9. Engelman JA. "Targeting PI3K signaling in cancer: opportunities, challenges and limitations." Nat Rev Cancer. 2009;9(8):550-562.   

10. Ihle NT, Powis G. "Inhibitors of phosphatidylinositol-3-kinase in cancer therapy." Mol Aspects Med. 2010;31(2):135-144. 

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.

Share this article:

Related Resources

You must be a registered member of Cancer Therapy Advisor to post a comment.
close

Next Article in General Oncology News

Sign Up for Free e-newsletters

CTA Community Poll

Regimen and Drug Listings

GET FULL LISTINGS OF TREATMENT Regimens and Drug INFORMATION

Bone Cancer Regimens Drugs
Brain Cancer Regimens Drugs
Breast Cancer Regimens Drugs
Endocrine Cancer Regimens Drugs
Gastrointestinal Cancer Regimens Drugs
Genitourinary Cancer Regimens Drugs
Gynecologic Cancer Regimens Drugs
Head and Neck Cancer Regimens Drugs
Hematologic Cancer Regimens Drugs
Lung Cancer Regimens Drugs
Other Cancers Regimens
Rare Cancers Regimens
Skin Cancer Regimens Drugs

More in General Oncology News

Second List of 'Choosing Wisely' Oncology Guidelines Released

Second List of 'Choosing Wisely' Oncology Guidelines Released

ASTRO recommendations indicate treatment options that should be discussed before being prescribed.

Cancer Survival at All-Time High Due to Targeted Drugs

Cancer Survival at All-Time High Due to Targeted ...

But aging population and increasing obesity threaten progress, notes American Association for Cancer Research.

Half of Cancer Staff Believe Dignified Death Possible In-Center

Half of Cancer Staff Believe Dignified Death Possible ...

But 95 percent of palliative care staff indicate that patients die with dignity in their wards.