The Lankenau Institute for Medical Research
Association: Resident Faculty
Despite technical advances, the main treatments that are used today to treat cancer (surgery, radiation therapy, and chemotherapy) reduce tumor burden, but are not curative in about half of cancer patients. Over half a million Americans continue to die from cancer every year. Most of these patients eventually die because the cancer spreads throughout the body using up all the body’s available energy. Successful treatment of metastatic disease is a great challenge because tumors can develop throughout the body, requiring administration of therapy to the entire patient rather than just to the cancer. Surgery is not always an option, or if used, will not remove every cancer cell. Alternatively, effective radiation and chemotherapy not only kill cancer cells but also many healthy cells leading to a high level of toxicity for the patient. Therefore, there is a great need for more effective and selective methods to destroy cancer cells.
Dr. Sawicki’s laboratory is developing new therapeutic strategies that hold great promise for improving the treatment of metastatic cancers, including prostate, ovarian, pancreatic, and cervical cancers. These strategies are based on the delivery of genetic material (i.e. DNA or RNA) to tumor cells exclusively to protect healthy cells from undesired damage. In one approach, DNA encoding diphtheria toxin is delivered to cancer cells. This is a safe and very powerful technology as only tumor cells die in response to targeted toxin production: the toxin is only produced inside cancer cells and does not affect other cells. To carry the genetic material inside cancer cells, extremely small particles called nanoparticles are being developed with our collaborators at MIT, Drs. Robert Langer and Daniel Anderson. In a second approach, nanoparticles deliver RNA rather than DNA to cancer cells. These special RNA molecules inhibit production of a specific protein required by tumor cells to survive. Dr. Sawicki and her colleagues recently demonstrated that both DNA- and RNA-based nanotherapy, effectively suppresses the growth of prostate and ovarian tumors. She is now testing these nanoparticles for their ability to kill pancreatic and cervical cancer cells. With minor modifications, she believes that nanotherapy can effectively treat additional cancers such as breast cancer.
Dr. Sawicki is applying lessons learned from her stem cell research to the nanoparticle therapy project. To this end, she is working to identify and isolate adult stem cells in the prostate. Adult stem cells can survive current standard therapies and are likely responsible for the development of aggressive prostate cancer. Using nanoparticle therapy to target the death of prostate stem cells holds promise as a new, effective and sustainable treatment for prostate cancer.
Approximately 30,000 men die from prostate cancer and 14,000 women die from ovarian cancer each year in the U.S. Despite technical advances, the main treatments used today to treat cancer -- surgery, radiation therapy, and chemotherapy -- reduce tumor burden but are not curative in about half of cancer patients, most of whom die because they have metastatic disease. Successful treatment of metastatic disease is a great challenge because tumors develop throughout the body, requiring systemic administration of therapy to the patient. Surgical procedures are impractical, and effective doses of radiation and chemotherapy therapy often damage or are toxic to normal cells.
Systemic delivery of targeted gene therapy holds great promise for improving the treatment of metastatic cancers, including prostate and ovarian cancer. Targeted therapy can be accomplished by restricting the delivery of DNA to specific cells and/or restricting the expression of genes to certain cell populations. In our laboratory, we are developing a gene therapy strategy to deliver and effectively target expression of a so-called suicide gene encoding diphtheria toxin, DT-A, to prostate and ovarian tumor cells. This toxin is an especially potent inhibitor of protein synthesis, so its expression in tumor cells results in their death. We are exploring ways to modify both viral and non-viral vectors to deliver the DT-A gene specifically to tumor cells and to neovasculature associated with tumors. A new class of polymers, poly(β-amino esters), developed at MIT by our collaborators, Drs. Robert Langer and Daniel Anderson, condense DNA into nanoparticles, and show promise as an effective new way to deliver DNA systemically to patients, while avoiding adverse toxicity and immunogenic responses associated with other vectors. We are also studying the utility of different genetic regulatory elements for targeting DT-A expression to prostate and ovarian tumor cells. We use transgenic mouse models for prostate and ovarian cancer, and imaging technologies (optical bioluminescence and microCAT) to test the efficacy of new therapeutic designs.
In related research, we are working to identify adult stem cells in the prostatic epithelium and fetal stem cells harbored by mothers after they have given birth. Identification of these cells will lay the groundwork for the development of cell therapy strategies for the treatment of cancer and other diseases in the future.
Dr. Sawicki's Google Scholar page
Burkhart RA, Peng Y, Norris ZA, Tholey R, Talbott VA, Liang Q, Ai Y, Miller K, Lal S, Cozzitorto JA, Witkiewicz AK, Yeo CJ, Gehrmann M, Napper A, Winter JM, Sawicki JA, Zhuang Z, Brody JR. Mitoxantrone targets human ubiquitin-specific peptidase 11 (USP11) and is a potent inhibitor of pancreatic cancer cell survival. Mol Cancer Res. 11(8):901-11, 2013.
Munne PM, Gu Y, Tumiati M, Gao P, Koopal S, Uusivirta S, Sawicki J, Wei GH, Kuznetsov SG. TP53 supports basal-like differentiation of mammary epithelial cells by preventing translocation of deltaNp63 into nucleoli. Sci Rep. 4:4663, 2014.
Danley J, Kwait R, Peterson DD, Sendecki J, Vaughn B, Nakisbendi K, Sawicki J, Lande L. Normal Estrogen, but Low Dehydroepiandrosterone Levels, in Women with Pulmonary Mycobacterium avium complex: A Preliminary Study. Ann Am Thorac Soc. 11(6):908-14, 2014.
Lal S, Burkhart RA, Beeharry N, Bhattacharjee V, Londin ER, Cozzitorto JA, Romeo C, Jimbo M, Norris ZA, Yeo CJ, Sawicki JA, Winter JM, Rigoutsos I, Yen TJ, Brody JR. HuR Posttranscriptionally Regulates WEE1: Implications for the DNA Damage Response in Pancreatic Cancer Cells. Cancer Res. 74(4):1128-40, 2014.