CT scans of the abdomen in another patient with advanced ovarian cancer, who had a em BRCA1 /em mutation (4693delAA), showed complete regression of a peritoneal tumor nodule over a 4-month treatment period with olaparib (200 mg, twice daily) for a year. Two genes or proteins are synthetically lethal when inactivation of either gene/protein is still compatible with cellular viability but inactivation of both leads to cell death [55]. of information about features distinguishing tumor from normal cells is being accumulated, resulting in frequent, major new insights into cancer biology. The bad news is usually that translating this information into the development of new treatments, or even refining the use of the ones we already have, has been much less impressive. Clinicians will attest that cytotoxic chemotherapy regimens, developed with the limited biological information available at the time of their development, remain the mainstay of treatment for most cancers. There are a few high-profile examples of rationally and molecularly targeted therapies, but we need to do much better if we are to shift the entire pattern of treatment to drugs that have high potency but mild side effects. A brief history of old-school and new age drug discovery Several articles have extensively reviewed the history of cancer drug development [1] and so here we will only pick out the salient points. It is widely accepted, although clouded by the secrecy of war [2], that this first tentative actions to treating cancer with drugs emanated from the observation that exposure to chemical warfare brokers (‘poison gases’), such as nitrogen mustards, could limit the proliferative nature of rapidly dividing lymphoid cells. Goodman and Gilman reasoned that this could translate into a therapeutic context and used the nitrogen mustard Prednisone (Adasone) mustine to treat a patient with non-Hodgkin’s lymphoma [3]. Around the same time, and building around the observation that this vitamin folic acid could stimulate acute lymphoblastic leukemia (ALL) cells, Farber used folate analogs such as aminopterin and then amethopterin (methotrexate) to treat ALL, in what is often heralded as the first ‘rational’ drug development approach [4]. Burchenal, Hitchings and Elion used a similar approach to assess the potential of purine analogs, identifying 6-mercaptopurine (reviewed in [5]). The nitrogen mustards and folate and purine analogs were much later shown to interfere with DNA replication, in part explaining their anti-tumor activity. In contrast, the alkaloids of the Madagascar periwinkle, such as vincristine, originally identified in the 1950s in a screen for anti-diabetic drugs, block tumor cell division, and therefore proliferation, largely by inhibiting microtubule polymerization [6]. All these therapies remain in clinical use today. Following the discovery of chemotherapeutics, the next significant advance came in the 1960s with the straightforward notion of combining drugs. The rationale for this came from the treatment of tuberculosis, for which antibiotics, each with a different mechanism of action, were more effective when used in combination. For cancer, it was considered that the development of resistance to a battery of agents used concurrently, rather than a single drug, was less likely. Using this approach, Holland, Freireich and Frei pioneered a combination of methotrexate and 6-mercaptopurine for treating children with ALL (reviewed in [7]). Today, most cancer chemotherapy regimens use this same paradigm. Anti-hormone Prednisone (Adasone) therapy has been spectacularly successful in the treatment of breast cancer. Tamoxifen, the most successful of these agents, was identified in the early 1960s as an estrogen receptor (ER) antagonist (more correctly, a selective estrogen receptor modulator). This drug, originally developed by Walpole’s group at ICI as a potential contraceptive, showed its potential when initially trialed for breast cancer in 1971 [8]. Subsequent clinical trials have confirmed the utility of this drug in ER-positive breast cancer patients and tamoxifen has now been given to millions of women and has saved countless lives. The impact of biology on cancer Prednisone (Adasone) drug development at this stage was limited; most therapies had been identified either by serendipity or had been selected primarily on the basis that they could limit cell division. However, in the 1970s and 1980s, the advent Prednisone (Adasone) of gene manipulation and molecular genetic analysis changed.Studies by Elledge and colleagues [60] and Hahn and colleagues [61] have also identified additional addictive effects in tumor cells that depend on RAS activity and similar work has elicited targets for MYC-driven cancers [62]. this information into the Shh development of new treatments, or even refining the use of the ones we already have, has been much less impressive. Clinicians will attest that cytotoxic chemotherapy regimens, developed with the limited biological information available at the Prednisone (Adasone) time of their development, remain the mainstay of treatment for most cancers. There are a few high-profile examples of rationally and molecularly targeted therapies, but we need to do much better if we are to shift the entire pattern of treatment to drugs that have high potency but mild side effects. A brief history of old-school and new age drug discovery Several articles have extensively reviewed the history of cancer drug development [1] and so here we will only pick out the salient points. It is widely accepted, although clouded by the secrecy of war [2], that the first tentative steps to treating cancer with drugs emanated from the observation that exposure to chemical warfare agents (‘poison gases’), such as nitrogen mustards, could limit the proliferative nature of rapidly dividing lymphoid cells. Goodman and Gilman reasoned that this could translate into a therapeutic context and used the nitrogen mustard mustine to treat a patient with non-Hodgkin’s lymphoma [3]. Around the same time, and building on the observation that the vitamin folic acid could stimulate acute lymphoblastic leukemia (ALL) cells, Farber used folate analogs such as aminopterin and then amethopterin (methotrexate) to treat ALL, in what is often heralded as the first ‘rational’ drug development approach [4]. Burchenal, Hitchings and Elion used a similar approach to assess the potential of purine analogs, identifying 6-mercaptopurine (reviewed in [5]). The nitrogen mustards and folate and purine analogs were much later shown to interfere with DNA replication, in part explaining their anti-tumor activity. In contrast, the alkaloids of the Madagascar periwinkle, such as vincristine, originally identified in the 1950s in a screen for anti-diabetic drugs, block tumor cell division, and therefore proliferation, largely by inhibiting microtubule polymerization [6]. All these therapies remain in clinical use today. Following the discovery of chemotherapeutics, the next significant advance came in the 1960s with the straightforward notion of combining drugs. The rationale for this came from the treatment of tuberculosis, for which antibiotics, each with a different mechanism of action, were more effective when used in combination. For cancer, it was considered that the development of resistance to a battery of agents used concurrently, rather than a single drug, was less likely. Using this approach, Holland, Freireich and Frei pioneered a combination of methotrexate and 6-mercaptopurine for treating children with ALL (reviewed in [7]). Today, most cancer chemotherapy regimens use this same paradigm. Anti-hormone therapy has been spectacularly successful in the treatment of breast cancer. Tamoxifen, the most successful of these agents, was identified in the early 1960s as an estrogen receptor (ER) antagonist (more correctly, a selective estrogen receptor modulator). This drug, originally developed by Walpole’s group at ICI as a potential contraceptive, showed its potential when initially trialed for breast cancer in 1971 [8]. Subsequent clinical trials have confirmed the utility of this drug in ER-positive breast cancer patients and tamoxifen has now been given to millions of women and has saved countless lives..