Fernando Arias-Mendoza - US grants

DESCRIPTION (provided by applicant): Non-Hodgkin's lymphoma (NHL) is the fifth most common type of cancer in the United States, and diffuse large B cell lymphoma (DLBCL) is its most common subtype. Until recently DLCBL was rapidly and inevitably fatal, but the new standard of treatment with multi-drug immuno-chemotherapy combinations makes this form of cancer potentially curable in 40% of patients. The last hope for the majority for whom standard treatment will fail lies in more radical therapies such as bone marrow transplant. These alternate treatments are more risky, especially for patients already weakened by a failed attempt at standard immuno-chemotherapy. There is thus a great need for information that could allow oncologists to individualize treatment and immediately begin radical therapy in those for whom standard treatment is likely to fail. We believe our non-invasive measurement of NHL tumor metabolism with magnetic resonance spectroscopy (MRS) can provide this information. During previous periods of grant support, we have obtained promising initial results showing that the pre-treatment metabolic ratio of phosphoethanolamine (Etn-P) and phosphocholine (Cho-P), normalized by the tumor content of nucleotide triphosphates (NTP), can sensitively and specifically predict treatment failure in DLBCL. The first aim for our multi-center study is to test our hypothesis that the [Etn-P + Cho-P]/NTP ratio is significantly correlated with treatment outcome in DLBCL. In addition to confirming our previous results with 31P MRS at the 1.5T field strength in an independent sample of patients, we also seek to extend these findings by studying the metabolism of DLBCL tumors with 31P at 3.0T, and also investigating absolute choline levels in DLBCL with 31P and 1H at both 1.5T and 3.0T. Our second aim is to follow up on initial indications that the significance of the correlation between the [Etn-P + Cho-P]/NTP ratio and treatment outcome is widely applicable to all forms of NHL and not merely the DLBCL subtype. We will approach this aim by accruing sufficient patients to analyze each subtype independently, using the 1.5T methods that are most directly applicable to the contemporary clinical environment. The proposed research is the final step leading a directed-therapy clinical trial and the culmination of an unprecedented program of translational research in MRS.

DESCRIPTION (provided by applicant): We recently have demonstrated that in vivo phosphorus magnetic resonance spectroscopy (31P MRS) provide metabolic signatures that predict treatment outcomes to standard treatment in non Hodgkin's lymphomas (NHL).1-9 The goal of the present proposal is to extend these results and demonstrate the value of 31P and hydrogen (1H) MRS at 3.0 Tesla acquired non-invasively and during the same visit in providing metabolic signatures to predict clinical outcome in NHL patients undergoing non-standard (experimental) treatment. If successful, these methods can be used to individually tailor the new treatments available for lymphoma patients with a potential increase in therapeutic success rates. Thus, the central aim of this proposal is to determine if the metabolic profiles determined non-invasively by in vivo 31P and 1H MRS are an independent a priori predictor of tumor therapy outcome in NHL patients, whom are going to receive non-standard therapy. Our clinical colleagues agree that successful achievement of this aim would help guide the use of more aggressive and novel therapies after a lymphoma patient has shown to be unresponsive to standard therapies. With the initial demonstration of our hypothesis in this proposal, we plan its extension into a multi-center research proposal aiming to accrue a larger patient cohort to formally validate the initial results. We believe that the expenses of the present proposal and its extension into a multi-center study are justified by the potential utility and economic impact of the results;namely to be able to tailor-fit novel therapies to the metabolic profile of an individual patient. We plan to study tumor areas of 30 non Hodgkin's lymphoma patients using noninvasive 31P and 1H MRS technology at 3.0 Tesla before and during the course of receiving non-standard therapy. We will follow-up the patients clinically to correlate the MRS results with objective measures of their therapeutic outcome namely long-term response to treatment and disease-free survival. In addition, the same tumor area of ten of these patients will be studied using 31P MRS at 1.5 Tesla before receiving therapy so a comparison factor can be found between the two magnetic field strengths. In this way, the data obtained at 1.5 Tesla can be compared with the data obtained at 3.0 Tesla. PUBLIC HEALTH RELEVANCE: In a previous work, we studied the chemistry of the tumors of patients with non-Hodgkin's lymphoma (a form of cancer of the lymph nodes) with a method called magnetic resonance spectroscopy that is non-invasive (meaning that it does not need x-rays, biopsies or needles). In the previous work, the chemistry of the tumors that we studied allowed us to predict if the tumor was going to respond to the drugs commonly given to treat the disease before the patients were treated. In the present work, we want to extend our findings by studying non-Hodgkin's lymphoma patients that already received the commonly given anti-cancer drugs and their tumor either failed to respond to treatment (the tumor did not go away) or came back once again, and that are now scheduled to receive non-standard (experimental) drugs. If we are successful, the non-invasive study of the chemistry of the tumors will allow us to predict and to follow-up whether or not the tumor is responding to the non-standard (experimental) treatment as we have predicted the response to standard treatment. This research will impact public health by identifying in advance if the patients with lymphoma will or will not respond to the newer treatment allowing doctors to tailor-fit the treatment on these patients by avoiding ineffective treatments preventing side-effects, waste of money, and waste of valuable time.