I think the recent conceptual strategy of targeting the DNA damage response has great potential for cancer therapies. This strategy hits at the cancer Achilles heel of defects at the replication-repair interface. So targeting the damage response in cancer cells provides an informed basis to use DNA damage as opposed to just overwhelming DNA repair by high levels of damage as is typically done by radiation or chemotherapies. Overwhelming repair does work for many cancers. Targeting specific DNA damage should be considerably better.

Very clever question, I'm not enough clever to answer it... Just my dream is targeted therapy, individual searching for all the possible markers for every patient, with the softest drugs applied. I don't see the possibility of on one leading path in cancer therapy.

We need to figure out the contribution of 99% of the human genome not the 1% protein encoding regions to cancer biology. It is really hard to expect current targeted therapy can really solve the problem now.

I recently learned that tumor cells "create" so many "wrong" proteins, not only the few from early ontogenesis we may know since decades, but so many deranged protein structures, that it is hard to beleive we do not already have a more general attempt to eradicate cancer just with a little treining lesson to our immune system to have it do its normal work, stop the tolerance against the tumor cells, which appear to differ in so many ways from "normal" cells - and, most likele, also from normal stem cells. Therefore I think many countries waste too much of tax payers money in so many wrong fields, but only limited amounts in immunology.

I agree with Rohan. Any Nobel Prize awarded in conjunction with cancer research will be for something that breaks open the entire field of cancer research. But probably not for something related to an individual cancer.

I like the idea of giving Nobel prizes to the people who make breakthrough cancer druGs ( and yes, I used to work in pharma). My former advisor, almost was singlehandedly responsible for driving all the kinase inhibitor efforts, and therefore was responsible for the discovery of inhibitors for kinases like HER2/EGFR, VEGFR, etc. I also like the idea of giving one to the discoverers of targeting angiogenesis, or any novel way to target cancer! as in the case of immunotherapies. I think the person(s) responsible for the first successful cancer vaccine, for example, may win.

If there becomes a universal cure, ie perhaps by targeting cancer stem cells, or even discovering those cells, then those individuals would be worthy of winning in my opinion.

Currently only one out of 20 cancer drugs makes it through phase III clinical trials successfully. I appreciate the blind men and the elephant point, but think we do need a more mechanistic understanding to complement systems biology knowledge. In the context of 300 cell types in humans predicting biological outcomes depends upon a detailed knowledge of macromolecular interactions and complexes and their activities that provides deep insights into the biology. Much of systems wide results and comprehensive sequencing is correlative rather than predictive. Michael Yaffe’s article (http://stke.sciencemag.org/cgi/reprint/sigtrans;6/269/pe13.pdf) makes this point about the scientific drunk and lamppost that defines an addiction to extensive sequencing data despite the relative lack of novel insight it provides. To achieve the necessary specificity and to avoid resistance to therapy we need to have mechanistic knowledge of the type that aids prediction of outcomes. Such knowledge would certainly merit a Nobel.

I think the recent conceptual strategy of targeting the DNA damage response has great potential for cancer therapies. This strategy hits at the cancer Achilles heel of defects at the replication-repair interface. So targeting the damage response in cancer cells provides an informed basis to use DNA damage as opposed to just overwhelming DNA repair by high levels of damage as is typically done by radiation or chemotherapies. Overwhelming repair does work for many cancers. Targeting specific DNA damage should be considerably better.

Ahed - You are correct that both normal and cancer tissue contains similar components and markers, such as estrogen and progesterone receptors. However hormones such as estrogen drive cancer in breast because they are essentially growth factors that counteract apoptosis. Mutations in virtually every DNA repair pathway can cause strong cancer predispositions, such as seen for BRCA1 and BRCA2 with breast cancer. The concept is that loss of DNA damage responses or other perturbations that impact genome integrity create a mutator phenotype as the principle driver for cancer by allowing the cancer cell to escape the selective pressures and regulation that prevent cancer in normal cells (see Cancer Res. 2001 Apr 15;61(8):3230-9). So there are many mutations associated with any given tumor but these multiple mutations derive from loss of genome stability that is most directly associated with DNA repair defects. Thus DNA repair defects are hallmarks of cancer cells and also an Achilles heel for cancer cell killing. This is because dividing cancer cells lack the tight checkpoint and damage responses that protect normal cells from mitotic catastrophe in the presence of DNA damage that causes replication fork stalling. So I predict that a breakthrough will come from a detailed mechanistic knowledge of DNA damage responses that allow their predetermined perturbation by chemical knock downs of specific DNA repair pathways.

Thanks John, really great comments. I think there are some tumor subtypes which should be considered as mutator phenotype, but not all.

Cancers are clonal and have multiple mutations so I would like to know of examples of cancers without genome instability.

I think several subtypes of medulloblastomas have been identified. If I remember correctly, one of four current subtypes is associated with p53 mutations and this is considered the mutator phenotype - I do not recall all the details, but dependent on the subtype, the optimal therapy may differ significantly to optimize the patients' long-term prognosis. Therefore, I can only assume very different levels of genome instability in several cancers. The major challenge in Cancer Research could be to Identity the Cancer stem cells, which should differ from normal stem cells mainly in their mutations.

Sorry, I am a bit sceptical that your approach of such an unspecific treatment for so many diseases could ever lead to a Nobel prize, although I could imagine, that hyperthermia - as an adjuvant for radiotherapy or chemotherapy may increase the benefit of radio- and chemotherapy - but I think there is not much evidence that moist heat alone should cure any cancer. And, heating some tumor or normal tissue and seeing an inflammatory reaction afterwards may not be surprising, that seems to be a natural reaction, but does not imply the cells would recognize specifically the tumor cells. I can imagine that a good immune reaction may need an "accident" like tissue destroyed by heat, or a scalpel, or bacterial or viral growth within a tumor to overcome tolerance (for example, an embryo can grow despite major histological incompatibility, but its growth is without "accident" of damaged tissue). The question remains, if those inflammatory cells in your moist heat approach really recognize tumor or just any normal cells after the heat accident and if they would fight only against the tumor - how should they know a heated antigen is from normal or tumor cell? Interestingly, during the last years, more and more evidences occured, that some immune cells within a tumor mass may even support tumor growth due to their production of some growth stimuli. In such cases, one may think about deleting those immune cells supporting tumor growth.

Maybe I am just speaking from a personal place - I think the focus for awarding Nobel prizes in the cancer arena should not lie in realm of single therapies (regardless of their nature). Instead our first focus should be on the philosophy of how we manage patients. For example, total patient management by a multidisciplinary team with minimally invasive accurate measures of metastasis (not intra or post operative -but preintervention.) No doubt that cancer is a Nobel cause...cancer therapy from an adjunct perspective is as well...but the idea of a single therapy (especially with regard to pharmaseuticals) from which all types of cancer patients will benefit, is unlikely at least, I think. I hesitate to say it's likely beyond our lifetimes (Perhaps not so much so beyond that of our children's), but again we must 1st perfect our approach to minimizing mortality through early detection, noninvasive techniques, definitive determination of malignancy and grade pre intervention and not treating patients with cookie cutter approaches. I recently went to a lecture series where at that institution, a team of oncologists, radiologists, nutritionists, internists, you name the specialty, meet for two or more hours as a group to review all aspects of previous care, all aspects pertaining to the current check up and imaging, etc and no decisions or therapeutic changes are made to that individuals therapeutic plan without consensus from the group. I digress, but really, that deserves the Nobel prize - we all know the disasters that can result from hasty care...the therapies are really limited in what they can do if not used in appropriate situations and their success relies on sound diagnoses and really early detection and intervention.