From Easter Island Soil to Treating Sarcoma—Rapamycin Derivatives

by

Danny McGurl

[Editor's Note: Danny has been battling high grade leiomyosarcoma since May 2004 and is currently undergoing chemotherapy. In his prior life, he was an avid hiker, backpacker and rock climber as well a competitive contract bridge player. He lives in Portland, OR with his wife and two year old daughter. He politely requests that all cancer researchers work faster. When he is not working as a senior systems analyst for Cingular Wireless, he can frequently be found posting on the yahoo LMSarcoma group.]

A brief history of Rapamycin and its derivatives

The story of Rapamycin starts almost 35 years ago, when a sample of soil was taken from Rapa Nui (Easter Island). Rapamycin was extracted from the soil and since the mid 1970s has been used as an anti-fungal agent. In the 1990s, Rapamycin was discovered to have immunosuppressive effects and in 1999 was approved under the brand Rapamune as an anti-rejection drug in kidney transplants. During the testing as a transplant rejection drug, anti-tumor effects were observed as well. Since then, three analogs of Rapamycin have been developed for use as anti-tumor agents: CCI-779 (Temsirolimus) by Wyeth, AP23573 by Ariad and RAD-001 (Everolimus) by Novartis.

CCI-779, AP23573 and RAD-001 are members of a class of drugs called "mTOR inhibitors". mTOR, (mammalian Target Of Rapamycin) is a cell-signaling protein that regulates the response of tumor cells to nutrients and growth factors, as well as controlling tumor blood supply through effects on Vascular Endothelial Growth Factor, VEGF. mTOR inhibitors starve cancer cells and shrink tumors by inhibiting the effect of mTOR. These drugs may well change the way that sarcomas and many other cancer types are treated.

[Editor's Note: The Vascular Endothelial Growth Factor, VEGF, is discussed in Dr. Keohan’s article, “What is angiogenesis and how does it play a role in cancer treatment?” In the February 2004 issue of ESUN.]

Why the excitement?

The first mTOR inhibitor trial was of CCI-779. In the Phase I trial three sarcoma patients had response with at least one experiencing significant shrinkage. In the later Phase I trial of AP23573, 5 of 5 sarcoma patients had an anti-tumor response. While these sample sizes are very small, it is still particularly encouraging because most patients in the trials had received extensive prior chemotherapy. The most promising result in the AP23573 study was in a Ewing's Sarcoma patient who had been through 9 prior chemo regimens. Over a 6 month period the patient experienced 75% shrinkage. A uterine sarcoma patient had over 12 months stability. Outcomes from the other cases have not been presented.

While no official data from the ongoing Phase II trials has been released, 2 leiomyosarcoma patients in the AP23573 trial report having over 6 months stability (although one has since withdrawn from the study due to side effects) and 2 additional leiomyosarcoma patients have completed their first cycles without progression and are continuing treatment.

Also encouraging is the news that the side effects found in both Phase I trials were generally mild. The dose escalation study revealed oral mucositis as the dose limiting toxicity (a class effect of mTOR inhibitors). Fortunately, complete mTOR inhibition occurs at drug levels below those that induced the worst side effects. Incredibly, despite Rapamycin's history as an immunosuppressant, the AP23573 trial did not show immunosuppression as a side effect and CCI-779 showed limited immunosuppression.

While the initial data is very promising, caution is warranted as there are two major unanswered questions. How durable will the responses to mTOR inhibitors be? In large scale tests what percentage of patients will respond? Ariad has submitted an abstract to the ASCO (American Society of Clinical Oncology) annual meeting in May, which may provide additional data on these important questions.

How it works

All mTOR inhibitors bind to the mTOR kinase. This has at least two important effects. First, mTOR is a downstream mediator of the PI3K/Akt pathway. The PI3K/Akt pathway is thought to be over activated in numerous cancers and may account for the widespread response from various cancers to mTOR inhibitors. The over activation of the upstream pathway would normally cause mTOR kinase to be over activated as well. However, in the presence of mTOR inhibitors, this process is blocked. The blocking effect prevents mTOR from signaling to downstream pathways that control cell growth. The interruption of the cell growth cycle may account for the fact that inhibitors are more likely to cause disease stability than shrinkage. Over activation of the PI3k/Akt kinase is frequently associated with mutations in the PTEN gene, which is common in many cancers and may help predict what tumors will respond to mTOR inhibitors. The second major effect of mTOR inhibition is anti-angiogenesis, via the lowering of VEGF levels.

In lab tests certain chemotherapy agents were found to be more effective in the presence of mTOR inhibitors. Additional lab results have shown that some rhabdomyosarcoma cells die in the presence of mTOR inhibitors. The complete functions of the mTOR kinase and the effects of mTOR inhibition are not completely understood.

All three drugs have similar anti-tumor mechanisms in blocking the mTOR kinase. However there are slight differences in the agents. CCI-779 was designed to be stable for IV administration. RAD-001 was designed to be taken orally. Both CCI-779 and RAD-001 combine in the body with the FKBP12 protein to form a molecule that blocks the mTOR kinase. In contrast, AP23573 is designed to be able to directly block the mTOR kinase. As a result, each drug may have different dosing requirements, side effects and clinical results.

Clinical trials

A study of AP23573 is currently the largest and least restrictive trial for sarcoma patients. This Phase II trial allows almost any type of sarcoma as long as certain restrictions are met. The trial is a combination trial for bone sarcomas, leiomyosarcoma, liposarcoma and all others. Each arm will be evaluated separately for possible Phase IIB and Phase III trials. Currently the arm for leiomyosarcoma is suspended for an interim review. It is scheduled to reopen in April. Depending on trial results, Ariad hopes to have Phase IIB or Phase III trials for additional sarcoma patients early in 2006. Additionally, Ariad has publicly announced plans to introduce an oral formulation of their drug by midyear. When the oral formulation is launched, they plan trials to test its efficacy against the current IV administration. Additionally, Ariad plans to open Phase IB trials to test AP23573 with both traditional chemo agents and molecularly targeted drugs. Lastly, Ariad is working on AP23481, a variant of AP23573 that will build up concentration in the bone. This should aid in the treatment of primary bone cancers including osteogenic and Ewing's sarcoma.

CCI-779 also has a Phase II trial for sarcoma and GIST, however it excludes sarcoma patients who have received previous chemotherapy for metastatic disease. There is a phase I trial for solid tumors using CCI-779 in combination with an EGFR inhibitor that may allow sarcoma patients. CCI-779 is currently being tested in both oral and IV administration. CCI-779 is currently in extensive trials for numerous other cancers including Phase III trials for renal and breast cancer. Since it is farthest along in the trial process for other forms of cancer, it may receive FDA approval earliest. Once it is FDA approved for any cancer, it could be used "off label" for treatment in sarcoma patients.

RAD-001 is developed by Novartis and is currently in phase I and Phase II trials for non-sarcoma related cancers. In a European trial of GIST patients it had limited results. The poor results from the GIST trial may be dosing related.

While current sarcoma trials of these inhibitors exclude patients with brain metastases, the drugs are being evaluated in treating brain tumors. This implies that inhibitors pass through the blood brain barrier and that CCI-779 and AP23573 might hold promise for sarcoma patients with brain metastasizes.

V2N2 ESUN Copyright © 2005 Liddy Shriver Sarcoma Initiative