Sonali M. Smith, MD
One of the major developments in cancer treatment in recent years has been the potential of drugs that target the oncogenic phosphatidylinositol- 3-kinase (PI3K)/Akt pathway and the mammalian target of rapamycin (mTOR), a downstream effector of the pathway. The intracellular pathway is central to cell proliferation, growth, and angiogenesis, so it’s no surprise that it’s implicated in a number of different tumor types, including breast, non-small cell lung, and renal cell cancer. Mutations and changes in expression have been found in every major node of the pathway. Typical mutations include mutation or amplification of PI3K, overexpression of the oncogene AKT, or inactivation of the tumor suppressor phosphatase and tensin homolog (PTEN). Research has shown that alteration of normal PI3K pathway signaling translates to a poor patient prognosis and resistance to available treatments. This makes the role of the PI3K pathway in tumor evolution particularly important to understand.
This multifunctional pathway has been recognized as a particularly attractive target for patients with lymphoma. “The PI3K pathway appears continuously deregulated among lymphoma malignancies,” said Sonali M. Smith, MD, director of the Lymphoma Program at the University of Chicago Medical Center, Illinois. Molecular ties linked to abnormal PI3K pathway signaling have been demonstrated in mantle cell lymphoma (MCL), a mature B-cell non-Hodgkin lymphoma, as well as in Hodgkin lymphoma. Specifically, mTOR, a serine/threonine kinase that is a key downstream target of the PI3K pathway, as well as an important regulator of normal development, has been associated with lymphomagenesis.
“[mTOR] appears to be an excellent target in MCL,” Smith said. “Overexpression of the protein cyclin D1 is the hallmark of mantle cell lymphoma. This protein is controlled in part by mTOR. So this is a very nice rationale for testing mTOR inhibitors in this cancer.” Smith added that the entire PI3K/Akt/ mTOR pathway, not just mTOR, is valid as a target in MCL.
Temsirolimus (Torisel, Pfizer), an mTOR inhibitor, has been studied in patients with MCL in phase II trials. The response rate in these trials was about 40% and lasted six months, according to Smith. This led to combination trials, including temsirolimus combined with rituximab (Rituxan, Genentech) and everolimus (Afinitor, Novartis) combined with the CHOP chemotherapy regimen.
In a phase III trial testing the efficacy of temsirolimus compared to choice of therapy in 162 heavily pretreated patients with relapsed or refractory MCL, temsirolimus significantly improved progression- free survival (hazard ratio [HR] = 0.44; P
= .0009) compared with the investigator’s choice. Objective response was 22% among patients receiving temsirolimus and 2% in the control group. The study established an effective clinical dose for temsirolimus monotherapy—the trial tested two different once-weekly dosages—and the results led to approval of the agent in Europe for relapsed or refractory MCL in 2009.
“The challenge with the classic mTOR inhibitors is that there is a lot of resistance,” said Smith, who was one of the investigators in the phase III study. It is not yet clear why only certain patients respond and why the responses are not durable. Smith believes that second-generation mTOR inhibitors, although still in early-stage trials, may be more promising for MCL.
Another approach that exploits the PI3K/mTOR pathway is targeting PI3 kinase, the major switch that signals to mTOR. The compound GS-1101 (Gilead) specifically inhibits the delta isoform of PI3K and is in clinical trials for MCL and other types of lymphoma. The compound has “a lot of activity” in MCL, according to Smith.
MCL is one of the most difficult-to -treat subtypes of non-Hodgkin lymphoma. Between 2% and 7% of all patients with non-Hodgkin lymphoma have MCL. The disease is often diagnosed at stage IV and is most common in men age 60 years and over. Because this older patient population is more likely to have comorbidities, they are not candidates for more intensive treatments, even though cytotoxic chemotherapy regimens—including rituximab and the chemotherapy regimen CHOP— appear to be effective in achieving a response, and even complete remission in many cases. Additionally, many patients relapse after receiving front-line treatments.
Hess G, Smith SM, Berkenblit A, Coiffier B. Temsirolimus in mantle cell lymphoma and other non-Hodgkin lymphoma subtypes. Semin Oncol. 2009; 36(suppl 3):S37-S45.