Good’s group

Deprivation in Cancer Biology – The Path to Highly Selective Treatment

Our group’s primary research focus is to investigate the biological response of cancer cells to varying amino acid deprivations, with the goal of elucidating the specific apoptotic mechanisms induced by such metabolic deficit(s).

Research Focus

Current cancer treatments are only modestly effective at curing cancer. Moreover, in some cases they have been shown to induce metastasis and even increase the probability of secondary malignancies. For those treatments which do successfully attack malignant cells, such therapeutic techniques often come with an associated loss of non-aberrant, normal cells (as observed with chemo- and radiation-driven hair loss, vomiting, etc.). Therefore, there exists a need to develop specific/targeted therapeutics for a wide range of cancers.

One such approach, which relies upon dietary restriction, has recently been gaining acceptance. Amino acid (AA) deprivation has been shown to effectively control malignant cell proliferation in vitro. Currently, such deprivation is commonly achieved through use of amino acid-degrading enzymes such as L-Asparaginase, Methioninase, and Arginine deiminase. Arginine deprivation, in particular, has recently garnered much attention for inducing apoptosis in cancer cells while having little to no detrimental effect upon normal cells. Clinical trials have subsequently confirmed this result in vivo.

Though effectual, this type of therapy is limited by the narrow spectrum of sensitive tumors and the appearance of therapy-resistant clones. Overcoming these limitations will require detailed knowledge of the molecular mechanisms which trigger cell death in sensitive tumors upon such deprivation. Although the cell is being deprived of a single AA, the effects resonate throughout multiple cellular processes which require the AA for use “as is” or in conjunction with other biomolecules. Such processes affected by Arginine deprivation include: 1) The AAs use as a single entity within the NO pathway; 2) Catabolism of Arginine as a source of Nitrogen for the cell; 3) Arginine employed in conjunction with other AAs for protein synthesis. Each of these processes has an intrinsic energetic value to the cell, with certain processes being preferentially regulated upon a deficit of a required reactant.

Goal

We seek to identify these key processes, thus providing inherent targets to increase the effectiveness of AA deprivation and prevent the appearance of therapy-resistant clones.

Approach/Techniques

Our lab exists at the interface of several areas of science, employing a wide range of investigative techniques taken from cell- and molecular biology as well as analytical chemistry.

  • Cell Biology

o   Cancer and primary cell culture

o   Classical light microscopy techniques and morphological assessment

o   Staining techniques, colorimetric assays, and fluorescence microscopy

  • Molecular Biology

o   Quantitative DNA/RNA analysis: qPCR, mRNA microarrays

  • Analytical Chemistry

o   Protein characterization and quantitation: LC-MS/MS, label-free quantitation

o   Single- and multivariate statistical analyses