Over decades it appeared to be very logic for patients and doctors to treat some cancers as aggressive as possible, i.e. removing as much tissue and related lymph nodes surgically and use all aggressive additional treatments possible to guarantee the best survival rate. This may still be the best for many cancers, but, as far as I understood, such highly aggressive therapies may not help in all cases, especially where there are already distant metastases or micrometastases. In such cases a too aggressive treatment may reduce the patients life quality without providing a benefit in life extension. Therefore, it will help to distinguish subsets of patient groups and offer a more individualized therapy, perhaps, depending on many other factors than the histological diagnosis, for example, some genetic and other markers which still may be investigated. And it also turned out that in some cases a patient could benefit from a more aggressive therapy, where a very restricted tumor was removed and further treatment did not appear necessary, but might have been beneficial due to early and unexpectable metastasis (when the basal membrane of the surrounding tissue was intact and no tumor cells appeared to break through - btw this supports the Cancer stem cell theory).

Resistance is one of the problems that can occur. I only know this for the melanoma field but there the new targeted molecular therapies can cause exactly this effect. They actually try to battle this by using combination therapies of different such drugs. The problem is first to have enough of them (which is really a problem, since the specialized drugs a coming now slowly on the market) and second to find the resistancies and then a way to prevent them (which also relies on having suitable drugs). The body has an amazing potential of bypassing blocked pathways. This will probably a big field for systems biology.

Another problem which you don't mention is the problem of potential cancer stem cells. The concept is discussed (sometimes quite controverse) but it seems that it has something. Under this every tumor would create a number of very slow growing cells (which are hard to target because of that property, since most therapies target fast grwoing cells) and then migrate through the body and either give rise to metastasis or new cancers.

There are 4 big issues: Multiple drug resistance, Selectivity, Toxicity and delivery.

The current drug targets are well defined and majorly chemotherapeutic agents targeting to only one target which stops the signalling from one pathway. But the pathway does crossing talking with each other which faciliated the signalling from the other pathways and diminishes the efficacy of used agent. Moreover on the bench-side everyday around 50 new inhibitors are designed and synthesized against the cancer. But still the selectivity is missing and their toxicity profile is high, which again pose a problem. However Delivery is again a critical point which limits the use the agents as cancer exhibit different micro-environment as compare to a normal cell.

But new rational drug designing like MDL approach or hybrid synthetic approach bring new inhibitors or agents which can act more than one target. This will assist in decreasing the incidences of these concerning problems but cant say they are sufficient to eradicate the problem.

CSC hypothesis suggests that relapse cases from current treatments are due to resistance by CSCs.

CSCs are the subset of cells in the primary tumor responsible for repopulating the tumor and forming metastasis. CSCs are more resistant to therapies than other cancer cells, and are rarely depleted. Even if the majority of the tumor mass is depleted by current treatments, without targeting CSCs you will have tumor relapse.

Strategies to target these cells will undoubtedly help reduce relapse.

Attached is a pretty cool article that demonstrates CSCs potential role in cancer development.

http://www.nature.com/nrc/journal/v13/n10/full/nrc3597.html

Over decades it appeared to be very logic for patients and doctors to treat some cancers as aggressive as possible, i.e. removing as much tissue and related lymph nodes surgically and use all aggressive additional treatments possible to guarantee the best survival rate. This may still be the best for many cancers, but, as far as I understood, such highly aggressive therapies may not help in all cases, especially where there are already distant metastases or micrometastases. In such cases a too aggressive treatment may reduce the patients life quality without providing a benefit in life extension. Therefore, it will help to distinguish subsets of patient groups and offer a more individualized therapy, perhaps, depending on many other factors than the histological diagnosis, for example, some genetic and other markers which still may be investigated. And it also turned out that in some cases a patient could benefit from a more aggressive therapy, where a very restricted tumor was removed and further treatment did not appear necessary, but might have been beneficial due to early and unexpectable metastasis (when the basal membrane of the surrounding tissue was intact and no tumor cells appeared to break through - btw this supports the Cancer stem cell theory).

More individualized therapies will certainly help reduce relapse in cancer treatmenta. By getting the patient's immune system involved has the greatest potential for combating cancer comebacks after formal treatment; this has been demonstrated with new vaccine like therapies.

http://www.cnn.com/2013/12/07/health/cohen-cancer-study/

Combination therapies are currently being used more successfully to treat cancer. Like viruses that mutate all the time, mutations occur in cancer resistance that can be potentially circumvented by using combination therapies that have multiple mechanism of actions. See the recent trials on lung cancer by visiting the NCI website on new clinical trials for example. Besides finding ways to obliterate stem cells, this is the major way forward in the near future to prevent cancer resistance to a single therapy. There are other possibilities such as with metalloproteinase inhibitors that block receptor cleavage, as some therapies such as herceptin, and antibody treatments rely on the receptors to be on the cell surface. But these strategies are in their infancy.

It seems that MDR inhibition or knockdown could be an irreversible method of reducing chemoresistance. There are many in vitro assays where this approach works, but does it work in animal models of cancer? MMP inhibitors worked well in vitro, but not in vivo.

Dear John (@johntainer)

I would be interested in your own views on this subject !

As you know, adopting a darwinian model of cancer from single founder cells to a heterogenous tumour which varies in both time and space and which evolves / become selected in response to treatment etc leads to treatment resistance. Another corollary of this is that the resistant tumour is very different to the original tumour in cell type. One can follow this evolution of resistance genetically e.g. N Engl J Med 2013; 369:1172-1173, Proc Natl Acad Sci U S A. 2008 March 18; 105(11): 4283–4288, Nature. 2012 January 18; 481(7381): 306–313.

Have attached the original Nowell 1976 paper in Science, which is still relevant

There have been many valuable responses above to John's excellent query, so I will confine myself to clarifying (1) some of the nuances involved in both the mechanisms of resistance, and of (2) overcoming resistance with some examples of recent notable successes, and in addition (3) will try to shed some much needed light on the frequent confusions surrounding relapse as true recurrence versus the emergence of a new primary (an issue raised within a perceptive comment by Rober Eibl), a matter of some considerable clinical importance. As always, I restrict the scope of evidence considered to only high-level evidence (ex vivo and above, critically human clinical data). Although I cover tradiitional areas, I am most concerned with the frontier edge of resistance stratgeies such as those surrounding Cancer Stem Cells (CSCs), microRNAs (miRNAs), and nanomedicine.

MULTIPLE MECHANISMS OF RESISTANCE AND SOME BREAKTHROUGHS

Drug resistance can be mediated by a number of different mechanisms (with different drugs and drug classes exhibiting different resistance mechanisms), principally:

1. INCREASE IN THE ACTIVITY OF ATP-DEPENDENT EFFLUX PUMPS

These are increases in efflux pumps such as adenosine-triphosphate- (ATP-) dependent transporters, in particular via overexpression of ATP-binding cassette (ABC) transporter proteins such as P-glycoprotein (P-gp), multidrug-resistance-associated protein 1 (MRP1), and breast cancer resistance protein (BCRP) - resulting in reduced intracellular drug concentrations. Agents that are substrates for P-gp and hence commonly associated with this type of resistance include anthracyclines, taxanes, antimetabolites, and vinca alkaloids (such as doxorubicin, daunorubicin, vinblastine, vincristine and paclitaxel) [1,2]. Note that MRP1 has been shown to confer resistance to anthracyclines and vinca alkaloids, but not taxanes [3].

In a meta-analysis of 31 breast cancer clinical trials, P-gp overexpression was associated with 3-fold increased risk of failure to respond to chemotherapy, P-gp expression was observed to increase after chemotherapy exposure [4]. Numerous efflux pump inhibitors, one of the best studied being tariquidar, a potent, specific, noncompetitive inhibitor of P-glycoprotein, which showed modest objective response in NSCLC and ovarian cancer [29] (and clinical activity to restore sensitivity to anthracycline or taxane chemotherapy in breast cancer).

2. REDUCTION OF CELLULAR DRUG UPTAKE:

Water-soluble drugs may attach to transporters carrying nutrients and therefore fail to accumulate within the cell. Resistance to drugs like cisplatin, and 5-FU is mediated by this mechanism [5].

3. CYTOCHROME P450 HEPATIC ENZYME SYSTEM:

Activation of regulated detoxifying systems such as the cytochrome P450 mixed function oxidases can lead to drug resistance in dozens of CYP-mediated agents by well-known pharmacokinetic mechanisms.

4. INCREASED DNA REPAIR:

Activation of mechanisms that repair drug-induced DNA damage are criticallly involved in acquired resistance. For example, it is known that platinum resistance is related to expression of DNA excision repair proteins, in particular ERCC-1.

As a practical example, a recent clinical trial [30] in platinum-resistant ovarian and peritoneal carcinoma patients used the 5-FU prodrug, gemcitabine (Gemzar) which is known to modulate ERCC1 nucleotide excision repair activity, and coupled it with cisplatin, to overcome resistance and produce an impressive ~43% objective response (partial and complete) in this refractory population.

5. DYSFUNCTIONAL APOPTOTIC PATHWAYS:

In addition, resistance can result from defective apoptotic pathways - such as the apoptosis-associated protein Bcl-2 - due to (1) malignant transformation [6], (2) a change in the apoptotic pathway during chemotherapy exposure, (3) in particular disruptions in apoptotic signaling pathways that decrease susceptibility to drug-induced cell death [7] including the anti-apoptotic Src pathway, or (4) changes in the cell cycle mechanisms that activate checkpoints and prevent initiation of apoptosis.

The pro-apoptotic Src inhibitor, dasatinib (Sprycel) has just been reported (at SABCS 2013, December) [31] to overcome endocrine resistance and reactivate apoptosis, more than doubling progression-free survival (PFS) in metastatic breast cancer patients.

6. DYSFUNCTION OF TUMOR SUPPRESOR GENES (TSGs):

That is, altered expression of tumor suppressor protein p53 which induces drug resistance. Here we have some positive findings from HDAC/DNMT inhibitors which have shown success in both preclinical and clinical studies, including in the large human clinical ENCORE 301 RCT [21].

7. PI3K/AKT/mTOR PATHWAY ACTIVATION:

Activation of the PI3K/AKT/mTOR pathway is frequently implicated in resistance to anticancer therapies, including biologics, tyrosine kinase inhibitors (TKIs), radiotherapy (RT), and cytotoxics.

For example, the incorporation of mTOR inhibitors has effectively, and dramatically, countered dysregulated signaling through the PI3K/PTEN/Akt/mTOR pathway and overcome numerous classes of drug resistance, especially endocrine resistance [16-20] where everolimus (Afinitor) has produced some of the most exciting recent results in HER2 and endocrine-positive breast cancer.

8. MICRORNAs (miRNAs):

The mechanisms for endocrine resistance are multiple and include deregulation of various components of the estrogen receptor (ER) pathway, alterations in cell cycle and cell survival signaling molecules, and the activation of escape pathways (such as the HER2 pathway), and dysregulation of miRNA expression has been associated with both preclinical and clinical endocrine therapy resistance, showing that miRNAs are pivotal to understanding the complex biological mechanism of endocrine resistance, and to effectively overcoming it [22].

So in this connection, a high level of miRNA-210 expression was observed to be associated with a higher risk of recurrence compared with lower levels, and miRNA-210 was shown to be associated with a poor clinical outcome in tamoxifen treatment, secondary to its association with endocrine resistance [23]. In addition, an association was demonstrated between high expression levels of, in particular, miRNA-30c and clinical benefit/longer progression-free survival (PFS) [24]. Furthermore, increasing levels of miRNA-26a were observed to be significantly associated with clinical benefit and prolonged time to progression (TTP) in ER-positive patients administered tamoxifen as first-line therapy of metastatic disease [25]. These findings are been further explored and extended in the MIRHO Trial in France (NCT01612871) in endocrine-positive breast cancer, as well as in prostate cancer (NCT01050504), and in a completed trial (results to appear) in lymphoma (NCT01606605), among many others.

9. CANCER STEM CELLS (CSCs):

Numerous reports implicate such cancer stem cells (CSCs) in the acquisition of drug resistance, with stem cell-like subpopulations being generally more refractory to drug treatment [8,9]. These and related studies have called into question the widely described 'hierarchical' model of cancer stem cells, in which the dogma (now effectively challenged) is held that stem cells can only arise from other stem cells, with the contrary demonstration that nonstem cells can spontaneously acquire stem cell properties [10,11], and cancer stem cells that have undergone EMT share properties associated with drug resistance [12,13]. Most intriguing is the fact that epithelial cells undergoing an EMT can actually acquire stem cell properties [14,15]. Note further that in the CSC model, rare populations of cancer stem cells possess tumor-initiating properties [26] and diverge from normal tissue stem cells through dysregulation of self-renewal pathways, enabling resistance via (1) modulation of molecular mechanisms, especially such as increased efficiency of DNA repair due to enhanced DNA damage response, (2) changes in cell cycle parameters, (3) overexpression of anti-apoptotic proteins or drug transporters (via ABC transporter expression or aldehyde dehydrogenase (ALDH) activity), and (4) B-cell lymphoma-2 (BCL2) related chemoresistance; and (5) by what I may call cycle-hiding due to their quiescent nature: namely, although the cell population is present it is difficult to target using traditional chemotherapies many (but not all of which) of which depend on active cell cycling [27], and activation of key signaling pathways [28].

Many agents can inhibit cancer stem cell (CSC) activity, including the anti--diabetic agent and mTOR inhibitor metformin, and we are awaiting the results of the recently completed Tufts Medical Center trial of metformin on colorectal cancer stem cells (CRC-CSCs) and nanomedicine is also showing considerable promise in this arena, as such in the use of "nanoshell technology" in the form of nanoparticle-mediated hyperthermia (NMT), under the trade name Aurolase, against CSC-harboring breast tumors (in clinical trial), as well as the use of a polymer-encapsulated curcumin nanoparticle formulation (NanoCurc) for the treatment of brain tumor stem cells, as well as other new and emerging nanoparticle platforms including liposomes, micelles, nanoemulsions, polymers, quantum dots, gold, iron-oxide, and dendrimers, among other exciting CSC-modulating strategies on the frontier-edge of research.

RELAPSE

Studies have shown that more than one-third of patients with metastatic breast cancer fail respond to first-line anthracyclines or taxanes and the development of drug resistance accounts for failure of treatment leading to death in more than 90% of patients with MBC [32], affecting all classes of agents (chemotherapeutics/cytotoxics, endocrine/hormonal, biological/targeted) [33]. It is important to understand that the time to relapse after initial chemotherapy is generally empirically divided into 6-month blocks, with refractory tumors demonstrating progression during or immediately following chemotherapy, and when the disease-free interval is brief (less than 6 - at most 12 months), it appears that acquired or intrinsic drug resistance is majorly responsible for tumor progression [34].

DISTINGUISHING RELAPSE AS TRUE RECURRENCE VERSUS NEW PRIMARY

It should be recognized that a significant portion of breast cancer patients who experience an ipsilateral relapse following conservative surgery and radiation therapy actually have new primary tumors rather than true local recurrences, and true recurrence and new primary tumor relapses have dramatically different natural histories, different prognoses, and consequently different implications for therapeutic management [35]. In this connection, we note that its been decisively demonstrated that patients with new primaries have better survival rates - in terms of overall survival (OS), distant disease-free survival (DDFS) and metastasis-free survival (MFS), with patients with a new primary having a 10- year overall survival of hovering around 90% compared to just above 60% for cases of true recurrence - than those with true recurrence, and this is true across malignancies, that new primaries systematically exhibit better prognoses and significantly improved survival outcomes than true recurrences, and new primaries - rather than true recurrences, account for a significant proportion of late relapses being de novo occurrences of breast carcinoma (true recurrences tend to occur earlier and are more highly associated with metastatic potential, stemming largely from residual surviving tumor clonogens) [36-42], so in answer to Robert Eibl's shrewd question re late relapse, although this can of course occur, the data suggests that late relapses are far more likely to be new primaries and not true recurrences, a prognostically favorable situation, so the discrimination between true recurrence and second primary tumor is of strong implication for optimal patient management.

METHODOLOGY OF THIS REVIEW

A search of the PUBMED, Cochrane Library / Cochrane Register of Controlled Trials, MEDLINE, EMBASE, AMED (Allied and Complimentary Medicine Database), CINAHL (Cumulative Index to Nursing and Allied Health Literature), PsycINFO, ISI Web of Science (WoS), BIOSIS, LILACS (Latin American and Caribbean Health Sciences Literature), ASSIA (Applied Social Sciences Index and Abstracts), SCEH (NHS Evidence Specialist Collection for Ethnicity and Health) and SCIRUS databases was conducted without language or date restrictions, and updated again current as of date of publication, with systematic reviews and meta-analyses extracted separately. Search was expanded in parallel to include just-in-time (JIT) medical feed sources as returned from Terkko (provided by the National Library of Health Sciences - Terkko at the University of Helsinki). A further "broad-spectrum" science search using SCIRUS (410+ million entry database) was then deployed for resources not otherwise included. Unpublished studies were located via contextual search, and relevant dissertations were located via NTLTD (Networked Digital Library of Theses and Dissertations) and OpenThesis. Sources in languages foreign to this reviewer were translated by language translation software.

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Development of drug resistance is a complex process as mentioned by Dr. Kaniklidis, and in fact from biological perspective gives survival chance/benefit for some cancer cells. Unfortunately from medical perspective this led to the clonal selection of resistant cancer cell lines. “How to effectively fight nature” is your question - really difficult one.