Modified bacteria and their uses thereof for the treatment of cancer or tumor
Described herein is a method of treatment of cancer or tumor using a modified bacteria or composition comprising the modified bacteria. In certain embodiments, the method is in combination with other treatment. In certain embodiments, the treatment is chemotherapy, radiation therapy, gene therapy, surgery or a combination thereof. The method makes modified facultative anaerobic bacteria into a conditional obligate anaerobe. The modified bacteria are strictly hypoxia regulated and comprise an essential gene expressing cassette. The vectors of this method comprise the essential gene expressing cassette. Also described herein are therapeutic and prophylactic compositions comprising the modified bacteria. The therapeutic and prophylactic compositions contain a purified form of the modified bacteria, while in certain embodiments, they do not contain other strain of microorganisms. The modified bacteria grow within the solid tumor/cancer, retarding its growth and are rapidly eliminated from normal tissues. The solid tumor/cancer includes breast cancer, liver cancer or neuroblastoma.
1. A method of making modified facultative anaerobic Salmonella typhimurium into an obligate anaerobe, wherein said facultative anaerobic Salmonella typhimurium comprise a strictly hypoxia regulated essential gene expressing cassette, wherein said cassette comprises: (a) a hypoxia conditioned promoter pepT activated by FNR and comprising an FNR binding site that is operatively linked to an essential gene that encodes an enzyme essential for cell wall formation; and (b) further comprises an antisense promoter sodA that is negatively regulated by FNR, and said obligate anaerobe reduces the growth of a solid breast or liver tumor when administered in vivo.
2. The method of claim 1 , wherein the obligate anaerobe is induced in the absence of diaminopimelic acid (DAP).
3. The method of claim 1 , wherein the essential gene is asd.
4. The method of claim 1 , wherein the hypoxia conditioned promoter is a forward anaerobic inducible promoter, and the antisense promoter is a reverse aerobic promoter.
5. The method of claim 4 , wherein the forward anaerobic inducible promoter is ansB or fdhF.
6. The method of claim 1 , wherein the strictly hypoxia regulated essential gene expressing cassette is chromosome-based.