Dietary asparagine limitation to augment immune therapy
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Non-technical overview of the research topic and relevance to breast cancer: The goal of this proposal is to
 determine if dietary changes can be used to increase the effectiveness of current treatments for breast cancer. Recently,
 we and others have shown that there are specific protein building blocks call non-essential amino acids (NEAAs), which
 are required for cancer cells to grow and resist cancer therapies. By definition NEAAs can be produced by the cells in our
 bodies, however they are also contained in the food we eat. Recently, we showed that when an NEAA called asparagine
 was removed from the diets of mice with breast cancer, the mice remained healthy but the cancer cells became unable to
 spread to other organs. Interestingly, we found that the breast cancer cells in mice receiving asparagine-low diets were
 unable to transform into “mesenchymal” cells. This transition is required for the cancer cells to travel from the breast to
 distant organs. Mesenchymal cells have also been associated with drug resistance in a number of cancers, opening the
 possibility that asparagine-low diets may be a possible treatment option to combine with existing cancer therapies..
 
 
 The question(s) or central hypotheses of the research: Recently, much attention has been payed towards a new
 class of cancer treatments known as immune therapies. Unlike traditional cancer drugs, which directly target the cancer
 cells, these therapies are designed to focus our immune system on attacking the tumor. Although these treatments have
 been used successfully to treat other cancers, they have proven relatively ineffective for breast cancer. One reason for this
 lack of success appears to be due to an ability of breast cancer cells to become mesenchymal, which as mentioned above
 is a type of cell that is resistant to treatment. We reason that if asparagine is required for cells to transform into these
 resistant cells, then it may be useful to have patients consume low asparagine diets while they are being administered
 immune therapy. In this proposal, we will test the hypothesis that low asparagine diets can be used in combination with
 immune therapy to treat patients with breast cancer..
 
 
 The general methodology: We will treat mice with breast cancer using an immune therapy called pembrolizumab.
 This drug blocks a communication pathway that cancer cells use to shield themselves from the immune system. Half of
 the mice will receive diets that contain no asparagine and half will receive normal diets. The effectiveness of the treatment
 will be measured based on whether the mice that are fed the low asparagine diets show increased tumor shrinkage as
 compared to mice that receive normal diets. Additionally, we will study the individual cells in these tumors to understand
 how different cell types change in response to the combined therapy. If the diet does not alter the outcome, these studies
 will allow us to understand why, and how me must alter our strategy. However, if the diet is successful in increasing the
 response to immune therapy, these later experiments will allow us to understand exactly how this occurs and how we can
 optimize the diet to increase its effectiveness..
 
 
 Innovative elements of the project and potential impact: Diet is one of the most direct factors influencing our
 health, however dietary manipulations have yet to be effectively applied towards treating cancer. Women with breast
 cancer are instructed to lead a healthy lifestyle, but should their diet follow what is prescribed for healthy individuals?
 General dietary restriction is linked with the prevention of cancer and reduced dietary intake is being investigated as a
 treatment for breast cancer. However, a severe limitation of this approach is that cancer patients are often in a fragile state,
 requiring them to consume adequate calories and essential nutrients to maintain general health. There is evidence that
 cancer cells require different nutrients than healthy cells. A archetypical example of one of these nutrients is asparagine.
 Here we will test the possibility of treating patients with diets that are designed to specifically starve cancer cells of the
 nutrients that they uniquely require to grow and resist therapy. If our hypothesis is proven correct, the next step towards
 implementing this strategy in patients would be to test whether low asparagine diets are safe in healthy humans, and
 whether they cause a decrease in the overall asparagine levels in their bodies. If these trials show that the diet is safe and
 effective at reducing asparagine levels, the final step would be to test the diets in patients that are being treated with
 immune therapy. We reason that our path to the clinic should take approximately two years as dietary changes are already
 being tested in patients and these treatments are not required to overcome the normal obstacles that traditional drugs face
 from the Food and Drug Administration.